Submissions for variant NM_000256.3(MYBPC3):c.964T>C (p.Trp322Arg)

gnomAD frequency: 0.00001  dbSNP: rs730880708

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766318	SCV000208405	uncertain significance	not provided	2016-10-04	criteria provided, single submitter	clinical testing	The Trp322Arg variant in the MYBPC3 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. Trp322Arg results in a non-conservative amino acid substitution of a non-polar Tryptophan with a positively charged Arginine at a residue that is conserved across species. In silico analysis predicts Trp322Arg is probably damaging to the protein structure/function. A variant in a nearby codon (Val321Met) has been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. In addition, the Trp322Arg variant was not detected in 488 alleles from control individuals of various ethnic backgrounds, indicating it is not a common benign variant. The variant is found in HCM panel(s).However, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000805929	SCV000945904	uncertain significance	Hypertrophic cardiomyopathy	2020-08-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972). ClinVar contains an entry for this variant (Variation ID: 181143). This sequence change replaces tryptophan with arginine at codon 322 of the MYBPC3 protein (p.Trp322Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223765	SCV000280290	uncertain significance	not specified	2014-09-01	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. p.Trp322Arg (c.964T>C) in the MYBPC3 gene Based on the data reviewed below, we consider this variant to be a variant of uncertain significance. This is a novel variant. This is a non-conservative amino acid substitution with a non-polar Tryptophan replaced with a polar Arginine. Tryptophan is highly conserved at this residue and in silico analysis (PolyPhen) predicts the amino acid change to be probably damaging to protein structure and function. A variant in a nearby codon (p.Val321Met) has been previously reported in association with cardiomyopathy (per GeneDx report, listed in HGMD). This variant is not listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 Genomes (http://www.1000genomes.org/) (as of November 15th, 2011). It is also not listed in the NHLBI Human Exome Variant database (http://evs.gs.washington.edu/EVS/base), which currently include data on ~5,000 individuals of Caucasian and African American ancestry. GeneDx reports that p.Trp322Arg was not observed in 244 presumably healthy individuals of mixed ancestry.