Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy
Abstract
1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Study Cohort
4.2. Genetic Analysis
4.3. Data Sources
4.4. Classification/Interpretation
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patient | Gene | Nucleotide | Protein | dbSNP | ClinVar | GnomAD (MAF%) | Classification (Year) | Classification 2023 |
---|---|---|---|---|---|---|---|---|
1 | TNNT2 | c.860G>A | p.Trp287Ter | rs727504247 | LP | NA | VUS (2016) | LP |
1 | TTN | c.47951G>A | p.Arg15984His | rs201774108 | VUSc | 0.0001 | VUS (2016) | VUS |
2 | TTN | c.73195G>A | p.Val24399Ile | rs1257567608 | NA | NA | VUS (2016) | VUS (VUS-LP) |
2 | TTN | c.57388C>T | p.Arg19130Cys | rs72646861 | LB | 0.827 | VUS (2016) | LB |
2 | TTN | c.53117C>T | p.Pro17706Leu | rs72646845 | LB | 0.369 | VUS (2016) | LB |
3 | ACTN2 | c.2051A>T | p.Asn684Ile | rs576783493 | VUSc | 0.0001 | VUS (2016) | VUS |
3 | TTN | c.93125G>A | p.Gly31042Asp | rs373754986 | VUS | 0.007 | VUS (2016) | VUS (VUS-LP) |
3 | TTN | c.76456G>C | p.Asp25486His | rs780958039 | VUS | 0.0008 | VUS (2016) | VUS (VUS-LP) |
4 | ACTN2 | c.1426G>A | p.Ala476Thr | rs142943120 | VUSc | 0.027 | VUS (2016) | VUS (VUS-LB) |
4 | TTN | c.57978del | p.Val19327PhefsTer10 | NA | NA | NA | VUS (2016) | VUS (VUS-LP) |
4 | TTN | c.76559G>A | p.Ser25520Asn | rs200450022 | VUSc | 0.061 | VUS (2016) | VUS (VUS-LB) |
4 | TTN | c.72764G>C | p.Gly24225Ala | rs114071241 | VUS | 0.001 | VUS (2016) | VUS (VUS-LP) |
4 | TTN | c.17066G>C | p.Gly5689Ala | rs200118743 | VUSc | 0.063 | VUS (2016) | VUS (VUS-LB) |
4 | TTN | c.4675G>A | p.Val1559Ile | rs538451328 | NA | 0.0003 | VUS (2016) | VUS (VUS-LP) |
5 | TTN | c.98971G>C | p.Glu32991Gln | rs199632397 | VUSc | 0.042 | VUS (2016) | VUS (VUS-LB) |
5 | TTN | c.27659G>A | p.Arg9220Gln | rs727504757 | VUS | 0.003 | VUS (2016) | VUS (VUS-LP) |
6 | TTN | c.45392G>A | p.Arg15131His | rs72646808 | VUSc | 0.185 | VUS (2016) | LB |
7 | TNNT2 | c.629_631del | p.Lys210del | rs45578238 | VUS | NA | VUS (2016) | VUS (VUS-LP) |
8 | MYH7 | c.1106G>A | p.Arg369Gln | rs397516089 | LP | 0.00006 | VUS (2016) | LP |
9 | TTN | c.73967A>G | p.Asn24656Ser | rs368443217 | VUSc | 0.008 | VUS (2016) | VUS (VUS-LB) |
9 | TTN | c.65012T>A | p.Met21671Lys | rs750298083 | VUSc | 0.004 | VUS (2016) | VUS |
9 | TTN | c.51830G>A | p.Arg17277His | rs201457934 | VUSc | 0.01 | VUS (2016) | VUS (VUS-LB) |
9 | TTN | c.9247G>A | p.Glu3083Lys | NA | NA | NA | VUS (2016) | VUS (VUS-LP) |
9 | MYH7 | c.2711G>A | p.Arg904His | rs397516165 | LP | 0.0001 | VUS (2016) | LP |
10 | DSP | c.1266+6G>T | NA | rs73375345 | LB | 0.037 | VUS (2016) | VUS (VUS-LB) |
10 | TTN | c.20920A>G | p.Ser6974Gly | rs72648980 | VUSc | 0.062 | VUS (2016) | VUS (VUS-LB) |
10 | VCL | c.2862_2864del | p.Leu955del | rs397517237 | VUSc | 0.021 | VUS (2016) | VUS (VUS-LB) |
11 | SCN5A | c.6010T>C | p.Phe2004Leu | rs41311117 | VUSc | 0.198 | VUS (2016) | LB |
12 | TTN | c.72970C>T | p.Gln24324Ter | NA | NA | NA | VUS (2016) | VUS (VUS-LP) |
13 | TTN | c.49249G>A | p.Asp16417Asn | rs1244503464 | NA | 0.0004 | VUS (2016) | VUS (VUS-LP) |
14 | TTN | c.12814G>T | p.Asp4272Tyr | rs72648940 | VUSc | 0.0005 | VUS (2016) | VUS |
15 | TTN | c.77076A>C | p.Glu25692Asp | rs370547473 | NA | 0.004 | VUS (2016) | VUS (VUS-LP) |
16 | TTN | c.32932C>A | p.Pro10978Thr | rs1393076582 | VUSc | NA | VUS (2016) | VUS |
17 | DES | c.179C>T | p.Ser60Leu | rs868853251 | NA | 0.0001 | VUS (2016) | VUS (VUS-LP) |
17 | TTN | c.46877G>A | p.Gly15626Asp | rs201802447 | VUS | 0.007 | VUS (2016) | VUS |
17 | TTN | c.1066G>C | p.Glu356Gln | rs144531477 | VUSc | 0.015 | VUS (2016) | VUS (VUS-LB) |
18 | TTN | c.95137A>G | p.Ile31713Val | rs758945559 | NA | 0.0008 | VUS (2016) | VUS (VUS-LP) |
18 | TTN | c.30484C>A | p.Pro10162Thr | rs532102837 | VUSc | 0.058 | VUS (2016) | VUS (VUS-LB) |
18 | DSP | c.6799A>T | p.Thr2267Ser | rs181378432 | LB | 0.009 | VUS (2016) | VUS |
18 | LMNA | c.1621C>T | p.Arg541Cys | rs56984562 | LP | 0.0001 | VUS (2016) | LP |
19 | RBM20 | c.1900C>T | p.Arg634Trp | rs796734066 | LP | NA | VUS (2016) | LP |
20 | DSP | del ex. 21_24 | NA | NA | NA | NA | VUS (2016) | VUS (VUS-LP) |
21 | MYH7 | c.1371A>G | p.Ile457Met | NA | NA | NA | VUS (2016) | VUS (VUS-LP) |
22 | TTN | c.94724T>C | p.Met31575Thr | rs397517786 | VUSc | 0.007 | VUS (2016) | VUS (VUS-LB) |
22 | TTN | c.62687G>T | p.Gly20896Val | rs549938348 | VUS | 0.0004 | VUS (2016) | VUS (VUS-LP) |
23 | RBM20 | c.1906C>T | p.Arg636Cys | rs267607002 | VUSc | 0.0001 | VUS (2016) | VUS |
24 | JPH2 | c.1736C>T | p.Pro579Leu | rs953353202 | VUS | 0.001 | VUS (2016) | VUS (VUS-LP) |
24 | RBM20 | c.1980C>A | p.Ser660Arg | NA | NA | 0.00007 | VUS (2016) | VUS (VUS-LP) |
25 | RBM20 | c.2200C>G | p.Arg734Gly | NA | NA | NA | VUS (2016) | VUS (VUS-LP) |
26 | TTN | c.57212G>A | p.Arg19071Gln | rs373282633 | VUS | 0.003 | VUS (2016) | VUS |
26 | TTN | c.48221T>A | p.Leu16074Gln | rs140714512 | VUSc | 0.051 | VUS (2016) | VUS (VUS-LB) |
26 | TTN | c.29645A>C | p.Lys9882Thr | rs760742068 | VUS | 0.001 | VUS (2016) | VUS (VUS-LP) |
27 | LMNA | c.1930C>T | p.Arg644Cys | rs1420000963 | VUSc | 0.201 | VUS (2016) | LB |
27 | TTN | c.77188C>T | p.Arg25730Trp | rs779581886 | VUS | 0.002 | VUS (2016) | VUS (VUS-LP) |
27 | TTN | c.60581T>C | p.Leu20194Pro | rs1359881893 | VUS | 0.0008 | VUS (2016) | VUS (VUS-LP) |
28 | RBM20 | c.1913C>T | p.Pro638Leu | rs267607003 | LP | 0.0003 | VUS (2016) | LP |
28 | TTN | c.74942C>T | p.Ala24981Val | rs749950083 | NA | NA | VUS (2016) | VUS (VUS-LP) |
28 | TTN | c.73501C>G | p.Pro24501Ala | rs770542451 | NA | 0.0004 | VUS (2016) | VUS (VUS-LP) |
28 | TTN | c.1333G>A | p.Ala445Thr | rs142414432 | VUSc | 0.021 | VUS (2016) | VUS (VUS-LB) |
29 | LMNA | c.1949A>G | p.Asn650Ser | rs775728847 | VUS | 0.0003 | VUS (2016) | VUS (VUS-LP) |
29 | TTN | c.38807A>G | p.Asn12936Ser | rs1184631064 | VUS | 0.0008 | VUS (2016) | VUS (VUS-LP) |
30 | ACTN2 | c.1040C>T | p.Thr347Met | rs727504590 | VUSc | 0.009 | VUS (2016) | VUS (VUS-LB) |
31 | RBM20 | c.3684A>G | p.Ter1228TrpextTer33 | rs1845123103 | NA | 0.0001 | VUS (2016) | VUS (VUS-LP) |
31 | TTN | c.40001G>A | p.Gly13334Glu | rs561284948 | VUS | 0.001 | VUS (2016) | VUS (VUS-LP) |
31 | TTN | c.20863C>T | p.Pro6955Ser | rs1438804317 | NA | NA | VUS (2016) | VUS (VUS-LP) |
32 | MYH7 | c.602T>C | p.Ile201Thr | rs397516258 | LP | 0.0001 | VUS (2016) | LP |
32 | TTN | c.71188G>A | p.Gly23730Arg | rs72648205 | VUSc | 0.034 | VUS (2016) | VUS (VUS-LB) |
33 | TTN | c.82400G>A | p.Arg27467His | rs199895320 | VUS | 0.002 | VUS (2016) | VUS (VUS-LP) |
33 | TTN | c.75575A>T | p.Asn25192IIe | rs200714263 | VUS | 0.002 | VUS (2016) | VUS (VUS-LP) |
34 | TTN | c.9139_9150del | p.Ser3047_Thr3050del | NA | NA | NA | VUS (2016) | VUS (VUS-LP) |
35 | ACTC1 | c.455-7C>T | NA | rs768363857 | LB | 0.003 | VUS (2017) | VUS |
35 | TTN | c.53791C>T | p.Arg17931Ter | rs869312112 | LP | NA | VUS (2017) | LP |
35 | TTN | c.33568T>G | p.Cys11190Gly | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
36 | TTN | c.58846G>A | p.Gly19616Ser | rs1262240030 | NA | NA | VUS (2017) | VUS (VUS-LP) |
36 | TTN | c.58590G>C | p.Gln19530His | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
36 | TTN | c.8320G>A | p.Glu2774Lys | rs763666119 | LB | 0.0003 | VUS (2017) | VUS (VUS-LP) |
37 | TNNI3 | c.-8G>A | NA | rs773513015 | VUSc | 0.001 | VUS (2017) | VUS |
37 | TTN | c.40796G>A | p.Arg13599Gln | rs778774812 | VUS | 0.001 | VUS (2017) | VUS (VUS-LP) |
38 | TTN | c.57709G>T | p.Val19237Leu | rs1397460981 | NA | NA | VUS (2017) | VUS (VUS-LP) |
39 | TTN | c.95967dup | p.Arg31990ThrfsTer10 | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
40 | TTN | c.12389G>A | p.Cys4130Tyr | rs375577529 | VUSc | 0.008 | VUS (2017) | VUS (VUS-LB) |
40 | VCL | c.2905G>A | p.Ala969Thr | rs199751261 | VUS | 0.002 | VUS (2017) | VUS (VUS-LP) |
41 | LMNA | c.253C>G | p.Leu85Val | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
41 | TTN | c.78602G>A | p.Gly26201Asp | rs756222422 | NA | 0.0004 | VUS (2017) | VUS (VUS-LP) |
41 | TTN | c.64137G>C | p.Lys21379Asn | rs56019808 | VUSc | 0.014 | VUS (2017) | VUS (VUS-LB) |
41 | TTN | c.36844+9A>G | NA | rs372725070 | LB | 0.013 | VUS (2017) | VUS (VUS-LB) |
41 | TTN | c.21355G>T | p.Ala7119Ser | rs200972189 | VUSc | 0.02 | VUS (2017) | VUS (VUS-LB) |
42 | TTN | c.92472G>C | p.Lys30824Asn | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
42 | TTN | c.25810C>T | p.Arg8604Ter | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
42 | TTN | c.28738+7T>G | NA | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
42 | TTN | c.14656A>T | p.Thr4886Ser | rs794727816 | VUS | NA | VUS (2017) | VUS (VUS-LP) |
43 | TNNC1 | c.400G>A | p.Glu134Lys | rs1553651640 | VUS | NA | VUS (2017) | VUS (VUS-LP) |
43 | TTN | c.95173A>G | p.Lys31725Glu | rs72629783 | VUSc | 0.021 | VUS (2017) | VUS (VUS-LB) |
43 | TTN | c.31709T>C | p.Ile10570Thr | rs72650057 | VUSc | 0.013 | VUS (2017) | VUS (VUS-LB) |
44 | TTN | c.56541G>A | p.Trp18847Ter | NA | LP | NA | VUS (2017) | VUS (VUS-LP) |
45 | FLNC | c.3612del | p.His1205ThrfsTer65 | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
46 | TTN | c.19570G>A | p.Asp6524Asn | rs72648973 | VUSc | 0.075 | VUS (2017) | VUS (VUS-LB) |
47 | TNNT2 | c.476G>A | p.Arg159Gln | rs45501500 | VUSc | NA | VUS (2017) | VUS |
48 | TTN | c.51369_51384del | p.Asp17123GlufsTer4 | NA | NA | NA | VUS (2017) | VUS (VUS-LP) |
49 | JPH2 | c.572C>G | p.Pro191Arg | rs554853074 | LB | 0.045 | VUS (2017) | VUS (VUS-LB) |
49 | TNNT2 | c.230C>T | p.Pro77Leu | rs144900708 | VUS | 0.003 | VUS (2017) | VUS (VUS-LP) |
50 | TTN | c.86270C>A | p.Ser28757Ter | NA | LP | NA | VUS (2017) | VUS (VUS-LP) |
50 | TTN | c.62666A>T | p.Asp20889Val | rs535816123 | NA | 0.002 | VUS (2017) | VUS (VUS-LP) |
50 | TTN | c.47435T>C | p.Ile15812Thr | rs72646819 | VUSc | 0.007 | VUS (2017) | VUS (VUS-LB) |
50 | TTN | c.16066A>G | p.Thr5356Ala | rs530353051 | VUS | 0.002 | VUS (2017) | VUS |
51 | BAG3 | c.903del | p.Arg301SerfsTer6 | NA | NA | NA | VUS (2018) | VUS (VUS-LP) |
51 | TTN | c.29327A>G | p.Tyr9776Cys | rs72650035 | VUSc | 0.02 | VUS (2018) | VUS (VUS-LB) |
52 | FLNC | c.1414del | p.Cys472ValfsTer20 | NA | NA | NA | VUS (2018) | VUS (VUS-LP) |
53 | MYH7 | c.5452C>T | p.Arg1818Trp | rs763073072 | VUS | 0.0005 | VUS (2018) | VUS (VUS-LP) |
54 | TNNC1 | c.394G>A | p.Asp132Asn | rs397516846 | VUS | 0.0003 | VUS (2018) | VUS (VUS-LP) |
55 | TTN | c.24617A>G | p.Asn8206Ser | NA | NA | NA | VUS (2018) | VUS |
55 | TTN | c.12889+7A>T | NA | rs10200398 | VUSc | 0.07 | VUS (2018) | VUS (VUS-LB) |
56 | TTN | c.20839G>A | p.Glu6947Lys | rs201326258 | VUS | 0.003 | VUS (2018) | VUS |
56 | VCL | c.1620T>G | p.Asp540Glu | rs533622785 | NA | 0.0006 | VUS (2018) | VUS (VUS-LP) |
57 | DSP | c.5673_5674dup | p.Lys1892ArgfsTer38 | NA | NA | NA | VUS (2018) | VUS (VUS-LP) |
57 | SCN5A | c.2924G>A | p.Arg975Gln | rs753149586 | VUS | 0.005 | VUS (2018) | VUS (VUS-LP) |
58 | TNNT2 | c.835G>A | p.Gly279Arg | rs757664792 | VUS | 0.0004 | VUS (2018) | VUS (VUS-LP) |
59 | TTN | c.9220C>T | p.Arg3074Ter | rs780706937 | VUSc | NA | VUS (2018) | VUS |
60 | TTN | c.81493+1G>T | NA | NA | NA | NA | VUS (2018) | VUS (VUS-LP) |
61 | TNNT2 | c.391C>G | p.Arg131Gly | rs74315380 | LP | NA | VUS (2019) | VUS (VUS-LP) |
62 | TTN | c.78412C>T | p.Arg26138Ter | rs794729384 | LP | 0.0004 | VUS (2019) | LP |
63 | TTN | c.67528G>T | p.Glu22510Ter | NA | NA | NA | VUS (2019) | VUS (VUS-LP) |
64 | TTN | c.39790C>T | p.Arg13264Ter | rs751746401 | LP | 0.0004 | VUS (2019) | LP |
65 | TTN | c.59787G>A | p.Trp19929Ter | NA | NA | NA | VUS (2019) | VUS (VUS-LP) |
65 | VCL | c.158A>G | p.Asn53Ser | rs751938777 | VUS | 0.001 | VUS (2019) | VUS (VUS-LP) |
2023 | Intronic | Indels | Nonsense | Missense | Total | ||
---|---|---|---|---|---|---|---|
B | 0 | 0 | 0 | 0 | 0 | ||
LB | 0 | 0 | 0 | 5 (4%) | 5 (4%) | ||
VUS | VUS-LB | 3 (2.4%) | 1 (0.8%) | 0 | 23 (18.4%) | 27 (21.6%) | 110 (88%) |
VUS | 2 (1.6%) | 0 | 1 (0.8%) | 13 (10.4%) | 16 (12.8%) | ||
VUS-LP | 2 (1.6%) | 10 (8%) | 7 (5.6%) | 48 (38.4%) | 67 (53.6%) | ||
LP | 0 | 0 | 4 (3.2%) | 6 (4.8%) | 10 (8%) | ||
P | 0 | 0 | 0 | 0 | 0 | ||
Total | 7 (5.6%) | 11 (8.8%) | 12 (9.6%) | 95 (76%) | 125 (100%) |
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Pérez-Serra, A.; Toro, R.; Martinez-Barrios, E.; Iglesias, A.; Fernandez-Falgueras, A.; Alcalde, M.; Coll, M.; Puigmulé, M.; del Olmo, B.; Picó, F.; et al. Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy. Int. J. Mol. Sci. 2024, 25, 3807. https://doi.org/10.3390/ijms25073807
Pérez-Serra A, Toro R, Martinez-Barrios E, Iglesias A, Fernandez-Falgueras A, Alcalde M, Coll M, Puigmulé M, del Olmo B, Picó F, et al. Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy. International Journal of Molecular Sciences. 2024; 25(7):3807. https://doi.org/10.3390/ijms25073807
Chicago/Turabian StylePérez-Serra, Alexandra, Rocío Toro, Estefanía Martinez-Barrios, Anna Iglesias, Anna Fernandez-Falgueras, Mireia Alcalde, Mónica Coll, Marta Puigmulé, Bernat del Olmo, Ferran Picó, and et al. 2024. "Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy" International Journal of Molecular Sciences 25, no. 7: 3807. https://doi.org/10.3390/ijms25073807
APA StylePérez-Serra, A., Toro, R., Martinez-Barrios, E., Iglesias, A., Fernandez-Falgueras, A., Alcalde, M., Coll, M., Puigmulé, M., del Olmo, B., Picó, F., Lopez, L., Arbelo, E., Cesar, S., Llano, C. T. d., Mangas, A., Brugada, J., Sarquella-Brugada, G., Brugada, R., & Campuzano, O. (2024). Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy. International Journal of Molecular Sciences, 25(7), 3807. https://doi.org/10.3390/ijms25073807