ClinVar Genomic variation as it relates to human health

proposed classification - variant undergoing re-assessment, contact laboratory

Reported in several unrelated individuals with HCM and one adult individual with unexplained sudden death in the published literature (Chung et al. (2007) Progress In Pediatric Cardiology 23 :33-38; PMID: 21511876, 25611685, 25351510, 28166282); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies suggest p.(G596R) appears to shift the balance of MYBPC3 interaction from actin to myosin (PMID: 38042491); This variant is associated with the following publications: (PMID: 25611685, 25351510, 28166282, 28518168, 25558701, 32746448, 16267253, 27930701, 33495597, 38042491, 32841044, 35130036, 37652022, 32461654, 21511876)

The c.1786G>A (p.Gly596Arg) MYBPC3 variant has been reported in our laboratory in a 59-year-old female patient with a clinical diagnosis of non-compaction dilated cardiomyopathy, with severe left ventricular dysfunction and with defibrillator. A nephew who died of sudden death at 45 years of age. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701). This variant is present in population databases (gnomAD allele frequency 0.0001032). ClinVar contains an entry for this variant (Variation ID: 42566). In silico analysis (CADD, PolyPhen-2, MutationTaster, SIFT y Provean) supports that this missense variant has a deleterious effect on protein structure/function, but this prediction has not been confirmed by functional studies. In summary, the available evidence for c.1054A>G (p.Arg352Gly) TP63 variant is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701), dilated cardiomyopathy (PMID: 32746448), or sudden death (PMID: 27930701). This variant has been identified in 21/203560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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.

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.

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.

This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701), dilated cardiomyopathy (PMID: 32746448), or sudden death (PMID: 27930701). This variant has also been identified in 21/203560 chromosomes (14/9070 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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