Submissions for variant NM_000256.3(MYBPC3):c.2543C>A (p.Ala848Glu)

dbSNP: rs730880569

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205147	SCV000261765	likely pathogenic	Hypertrophic cardiomyopathy	2022-10-03	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala848 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 23816408, 25740977, 33782553), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 220872). This missense change has been observed in individuals with hypertrophic or dilated cardiomyopathy (PMID: 25740977, 28408708, 28416588; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 848 of the MYBPC3 protein (p.Ala848Glu).
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000205147	SCV001156272	uncertain significance	Hypertrophic cardiomyopathy	2018-09-18	criteria provided, single submitter	research	This MYBPC3 Ala848Glu variant has been reported in 1 patient with HCM (Calore, et al., 2015) and 1 patient with DCM (Dal Ferro M, et al., 2017). It is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect, but no prediction is called by PolyPhen-HCM. We have identified this MYBPC3 Ala848Glu variant in 1 HCM patient (Ingles J, et al., 2017) and the variant was found to segregate to 3 affected family members (4 meiosis). Interestingly different variants at the same amino acid position (Ala848Gly and Ala848Glyfs*) have been reported in cardiomyopathies. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is rare in the general population (PM2), segregates with disease (PP1), in silico tools predict aberrant splicing to occur (PP3) and has been identified in a total of 3 probands (PS4_supporting), therefore we classify MYBPC3 Ala848Glu as a variant of "uncertain significance".
GeneDx	RCV000786361	SCV002538831	uncertain significance	not provided	2022-06-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17643520, 25740977, 28416588, 31514951, 28408708, 28790153)
Mayo Clinic Laboratories, Mayo Clinic	RCV000786361	SCV002541138	uncertain significance	not provided	2021-10-20	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786361	SCV000925157	uncertain significance	not provided	2018-01-12	no assertion criteria provided	provider interpretation	Variant MYBPC3 p.Ala848Glu c.2543C>A in exon 24 (NM_000256.3, hg19 chr11-47359001-G-T) SCICD classification variant of uncertain significance, probably disease causing We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: MYBPC3 missense variant, so need stronger evidence for pathogenicity. Sufficiently rare, need more cases or more segregation. Case data summary Reported in 4 presumably unrelated cases of HCM (not including the patient) and 1 case of DCM. There's weak segregation data. Please see below for a detailed review of case data. Population Data There is no variation at this codon in gnomAD. Metrics indicate adequate coverage (median coverage 66x for exomes, 33x for genomes). However, there is one individual listed with this variant in ExAC (1/4298 East Asian individuals (MAF 0.01163%), per varsome.com Case data: 1. HCM Melacini et al 2008 (lab report suggests likely redundant with Calore et al 2015) Variant seen in a 40yo male with HCM, obstruction, gradient, positive family history No data on segregation Recruited in Padua, Italy 2. HCM Meyer et al 2013 Variant seen in a patient with HCM No segregation data Recruitment: University of Marburg, Germany 3. HCM Ingles et al 2017 (presumably redundant with Burns et al 2017) Variant seen in a patient with HCM No data on segregation provided Recruited in Sidney, Australia 4. HCM Internal lab data, two affected family members have this variant. Other: 1. DCM Dal Ferro et al 2017 Variant seen in a patient with dilated cardiomyopathy. Insufficient data provided to assess whether patient has burntout HCM. Also carries another missense variant in MYBPC3 Authors classify p.Ala848Glu as likely pathogenic, rationale and data supporting classification not provided Recruited in Italy (Trieste Heart Muscle Disease Registry)