Submissions for variant NM_000256.3(MYBPC3):c.2543C>G (p.Ala848Gly)

dbSNP: rs730880569

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158169	SCV000208104	uncertain significance	not provided	2013-01-25	criteria provided, single submitter	clinical testing	This variant is denoted p.Ala848Gly (GCG>GGG): c.2543 C>G in exon 25 of the MYBPC3 gene (NM_000256.3). The Ala848Gly variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Ala848Gly results in a conservative amino acid substitution of one non-polar amino acid, this residue is conserved across species. In silico analysis predicts Ala848Gly is probably damaging to the protein structure/function. Mutations in nearby codons (Tyr847His, Ser858Asn) have been reported in association with HCM, supporting the functional importance of this region of the protein. Additionally, the Ala848Gly variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Ala848Gly is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001178352	SCV001342767	uncertain significance	Cardiomyopathy	2023-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 848 of the MYBPC3 protein. Computational prediction suggests that this variant may have a 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 one individual affected with hypertrophic cardiomyopathy (PMID: 30297972, 32841044, 33782553). This variant has been identified in 2/247484 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.
Ambry Genetics	RCV002426772	SCV002740603	uncertain significance	Cardiovascular phenotype	2023-08-08	criteria provided, single submitter	clinical testing	The p.A848G variant (also known as c.2543C>G), located in coding exon 25 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 2543. The alanine at codon 848 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484970	SCV002786260	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-12-27	criteria provided, single submitter	clinical testing
Invitae	RCV003748192	SCV004375806	uncertain significance	Hypertrophic cardiomyopathy	2023-05-30	criteria provided, single submitter	clinical testing	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 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. This variant disrupts the p.Ala848 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25740977, 28408708, 28416588; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 180975). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33782553). This variant is present in population databases (rs730880569, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 848 of the MYBPC3 protein (p.Ala848Gly).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000158169	SCV001742796	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158169	SCV001953840	uncertain significance	not provided		no assertion criteria provided	clinical testing