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

gnomAD frequency: 0.00076  dbSNP: rs370890951

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	RCV000476215	SCV000208169	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV000244315	SCV000319934	likely benign	Cardiovascular phenotype	2019-01-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087603	SCV000558139	likely benign	Hypertrophic cardiomyopathy	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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 Center for Human Genetics Tuebingen	RCV000476215	SCV001148269	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MYBPC3: BP4, BS2
Illumina Laboratory Services, Illumina	RCV001104837	SCV001261731	uncertain significance	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 Laboratory Services, 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	RCV000476215	SCV001474261	likely benign	not provided	2023-10-09	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157319	SCV000207054	likely benign	Cardiac arrest	2014-09-04	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000476215	SCV001743755	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000476215	SCV001926237	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000476215	SCV001930446	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000476215	SCV001952605	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000476215	SCV001974807	likely benign	not provided		no assertion criteria provided	clinical testing
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	RCV001087603	SCV005374570	likely benign	Hypertrophic cardiomyopathy		no assertion criteria provided	research