Submissions for variant NM_000256.3(MYBPC3):c.2479C>A (p.Gln827Lys)

dbSNP: rs375322174

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158161	SCV000208096	uncertain significance	not provided	2014-04-22	criteria provided, single submitter	clinical testing	The Q827K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q827K variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, missense mutations in nearby residues (R820W, R820Q, E832G, A833T) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. The Q827K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, the Q827K substitution occurs at a position that is not conserved across species (K827 is present in many species including chicken). Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (CirinoA et al., 2011; Hershberger R et al., 2009). The variant is found in CARDIOMYOPATHY panel(s).
Color Diagnostics, LLC DBA Color Health	RCV000778005	SCV000914114	uncertain significance	Cardiomyopathy	2024-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 827 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 38489124) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 29447731, 33500567). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001303287	SCV001492527	uncertain significance	Hypertrophic cardiomyopathy	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 827 of the MYBPC3 protein (p.Gln827Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 180971). 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 tolerated. 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.
Ambry Genetics	RCV002453535	SCV002738324	uncertain significance	Cardiovascular phenotype	2024-02-25	criteria provided, single submitter	clinical testing	The p.Q827K variant (also known as c.2479C>A), located in coding exon 25 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 2479. The glutamine at codon 827 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000158161	SCV004236666	uncertain significance	not provided	2023-06-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001303287	SCV004839254	uncertain significance	Hypertrophic cardiomyopathy	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 827 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 38489124) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 29447731, 33500567). This variant has not been identified 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.