Submissions for variant NM_000256.3(MYBPC3):c.1238A>G (p.Glu413Gly)

dbSNP: rs730880532

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158069	SCV000208004	uncertain significance	not provided	2020-10-30	criteria provided, single submitter	clinical testing	Observed in association with HCM in the published literature (Ho et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30297972)
Invitae	RCV001850204	SCV002295539	uncertain significance	Hypertrophic cardiomyopathy	2022-09-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 413 of the MYBPC3 protein (p.Glu413Gly). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33782553). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 180926).
Fulgent Genetics, Fulgent Genetics	RCV002478475	SCV002793402	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-29	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223683	SCV000280209	uncertain significance	not specified	2014-07-22	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Glu413Gly Based on the data reviewed below we consider this variant as a variant of uncertain significance. This variant is novel and has not been reported previously as a disease mutation or as a benign polymorphism. Glu413Gly results in a non-conservative amino acid substitution of a negatively charged Glutamic acid residue with an uncharged, non-polar Glycine residue at a position that is conserved through zebra fish. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging with a score of 0.998. Mutation Taster predicts the variant to be deleterious with a score of 98. The Glutamic acid at codon 413 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Gly407Ser; Ser408Asn; Gly416Ser). In total the variant has not been seen in ~6,000 individuals from publicly available population datasets. There is no variation at codon 413 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,000 Caucasian and African American individuals (as of 5/31/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 5/31/13).