Submissions for variant NM_000256.3(MYBPC3):c.815G>A (p.Arg272His)

gnomAD frequency: 0.00002  dbSNP: rs759515993

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493976	SCV000583384	uncertain significance	not provided	2017-05-21	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The R272H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, in silico analysis predicts the R272H variant is probably damaging to the protein structure/function. Nevertheless, R272H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to arginine (R) are tolerated across species and histidine (H) is the wild-type residue at this position in at least one mammalian species. Furthermore, although a missense variant at the same residue (R272C) has been reported in HGMD in association with cardiomyopathy (Zeller et al., 2006; Hershberger et al., 2010; Millat et al., 2010), the clinical significance of this variant also remains to be definitively determined.
Invitae	RCV000553265	SCV000623623	uncertain significance	Hypertrophic cardiomyopathy	2022-07-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 272 of the MYBPC3 protein (p.Arg272His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 31918855). ClinVar contains an entry for this variant (Variation ID: 430553). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001805112	SCV002051920	uncertain significance	Cardiomyopathy	2022-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 272 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/207620 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.