ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3392T>C (p.Ile1131Thr) (rs370890951)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035586 SCV000059236 likely benign not specified 2015-04-27 criteria provided, single submitter clinical testing p.Ile1131Thr in exon 31 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 0.3% (14/4490) of Finnish chromo somes and 0.15% (72/48504) of European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs370890951). Additionally, isoleucine (Ile) at position 1131 is not conserved in mammals or evolutionarily distant species and 1 mammal (prairie vole) carries a threonine (Thr) at this po sition, supporting that this change may be tolerated.
GeneDx RCV000035586 SCV000208169 likely benign not specified 2018-03-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000244315 SCV000319934 likely benign Cardiovascular phenotype 2019-01-02 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
Invitae RCV001087603 SCV000558139 likely benign Hypertrophic cardiomyopathy 2020-12-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000777749 SCV000913711 likely benign Cardiomyopathy 2018-04-13 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845377 SCV000987435 likely benign Left ventricular noncompaction criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000476215 SCV001148269 likely benign not provided 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001104837 SCV001261731 uncertain significance Familial hypertrophic cardiomyopathy 4 2018-03-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001104838 SCV001261732 benign Left ventricular noncompaction 10 2018-03-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000777749 SCV001333808 benign Cardiomyopathy 2017-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035586 SCV001363105 benign not specified 2021-03-25 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.3392T>C (p.Ile1131Thr) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 272528 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3392T>C has been reported in the literature as a non-informative finding in hypertrophic cardiomyopathy cohorts (example, Alders_2003, Mook_2013, VanDriest_2004, Salazar-Mendiguchia_2020), dilated cardiomyopathy cohorts (example, Haas_2015), SIDS cohorts undergoing multigene panel testing (example, Brion_2012) and within the ESP cohort (Andreasen_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least two reports of a co-occurrence with another pathogenic variant have been reported (MYBPC3 c.2373dupG, p.Trp792fsX41, Alders_2003, Mook_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority concordance as likely benign (n=7)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287560 SCV001474261 likely benign none provided 2019-10-07 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157319 SCV000207054 likely benign Cardiac arrest 2014-09-04 no assertion criteria provided clinical testing

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