Submissions for variant NM_000256.3(MYBPC3):c.3373G>A (p.Val1125Met)

gnomAD frequency: 0.00004  dbSNP: rs121909378

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000534928	SCV000198809	uncertain significance	Hypertrophic cardiomyopathy	2019-04-05	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in one infant who died of SIDS (Dewar 2017). It was also reported in one Iranian individual with DCM where an in silico study showed that it might be pathogenic (Mahdieh 2018). The variant has also been reported in a patient who was compound het for this variant and the c.960-1G>C variant. Her brother also had both variants and was affected but her mother and son who only had the c.906-1G>C variant were unaffected. Her nephew who had just the V1125M variant was mildly affected (Frank-Hansen 2008). Classified as VUS favour pathogenic in Walsh 2017. Clinvar: VUS (GeneDx, Invitae). Gnomad: 0.01% (1 allele).
GeneDx	RCV000766371	SCV000208167	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy and sudden unexplained death; however, detailed clinical information was not provided in all cases and additional cardiogenetic variants were identified in some patients (Frank-Hansen et al., 2008; Dewar et al., 2017; Walsh et al., 2017; Mahdieh et al., 29018; Gomez et al., 2017; Stava et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 27532257, 28807990, 29493010, 22267749, 28356264, 31376648, 34426522, 33782553, 35653365, 27585509, 18337725)
Invitae	RCV000534928	SCV000623593	likely pathogenic	Hypertrophic cardiomyopathy	2023-08-29	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with MYBPC3-related conditions (PMID: 28356264, 29493010, 33782553; Invitae). This variant is present in population databases (rs121909378, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1125 of the MYBPC3 protein (p.Val1125Met). ClinVar contains an entry for this variant (Variation ID: 8604). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001179577	SCV001344271	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1125 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 28356264, 32841044, 33782553). Some of these individuals also carried a different pathogenic variant in the same gene (PMID: 22267749). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29493010), in an individual affected with suspected drug-induced long QT syndrome (PMID: 31376648), and in an individual affected with sudden unexplained death (PMID: 28807990). This variant has been identified in 7/273636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002453252	SCV002616827	uncertain significance	Cardiovascular phenotype	2023-02-28	criteria provided, single submitter	clinical testing	The p.V1125M variant (also known as c.3373G>A), located in coding exon 31 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3373. The valine at codon 1125 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in sudden unexplained death and hypertrophic cardiomyopathy (HCM) cohorts; however details were limited and some HCM reports may overlap (Dewar LJ et al. Circ Cardiovasc Genet, 2017 Aug;10; G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mazzarotto F et al. Genet Med. 2019 Feb;21(2):284-292; Helms AS et al. Circ Genom Precis Med. 2020 Oct;13(5):396-405). This variant co-occurred with a second MYBPC3 variant in affected members of a family with HCM, while the p.V1125M variant occurred alone in one individual with a borderline diagnosis of hypertrophy (Frank-Hansen R et al. Eur. J. Hum. Genet., 2008 Sep;16:1062-9). This variant has also been detected in an individual with dilated cardiomyopathy (Mahdieh N et al. J. Clin. Lab. Anal., 2018 Mar). This variant was reported in an individual with Fabry disease and HCM who also had a GLA mutation and a second MYBPC3 variant (Favalli V et al. J. Am. Coll. Cardiol., 2016 09;68:1037-50). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009135	SCV003804691	uncertain significance	Hypertrophic cardiomyopathy 4	2023-01-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000534928	SCV004836604	uncertain significance	Hypertrophic cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1125 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 28356264, 32841044, 33782553). Some of these individuals also carried a different pathogenic variant in the same gene (PMID: 22267749). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29493010), in an individual affected with suspected drug-induced long QT syndrome (PMID: 31376648), and in an individual affected with sudden unexplained death (PMID: 28807990). This variant has been identified in 7/273636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
OMIM	RCV000009135	SCV000029352	pathogenic	Hypertrophic cardiomyopathy 4	2008-09-01	no assertion criteria provided	literature only