Submissions for variant NM_000256.3(MYBPC3):c.3771C>A (p.Asn1257Lys)

dbSNP: rs730880603

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766381	SCV000208196	likely pathogenic	not provided	2024-08-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect in HEK293A cells (PMID: 32841044); 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: 23396983, 24510615, 24793961, 27532257, 12818575, 25351510, 29030401, 33782553, 32841044, 37652022)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215436	SCV000271995	uncertain significance	not specified	2016-01-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asn1257Ly s variant in MYBPC3 has been reported in at least 7 individuals with HCM (Lopes 2013, Kapplinger 2014, Lopes 2015). This variant was absent from large populatio n studies. Computational prediction tools and conservation analysis suggest that the p.Asn1257Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some s uspicion for a pathogenic role, the clinical significance of the p.Asn1257Lys va riant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234005	SCV000284245	pathogenic	Hypertrophic cardiomyopathy	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1257 of the MYBPC3 protein (p.Asn1257Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with known and suspected hypertrophic cardiomyopathy (HCM) (PMID: 23396983, 24510615, 24793961, 27532257, 29030401; internal data). ClinVar contains an entry for this variant (Variation ID: 181022). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 32841044). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845509	SCV000987611	likely pathogenic	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345534	SCV002623409	uncertain significance	Cardiovascular phenotype	2023-12-08	criteria provided, single submitter	clinical testing	The p.N1257K variant (also known as c.3771C>A), located in coding exon 33 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3771. The asparagine at codon 1257 is replaced by lysine, an amino acid with similar properties. This variant has been observed in multiple individuals reported to have hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10:[Epub ahead of print]). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000215436	SCV000280269	uncertain significance	not specified	2013-10-01	no assertion criteria provided	clinical testing	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. MYBPC3 p.Asn1257Lys Based on the data reviewed below we classify this variant as a variant of uncertain significance that is likely disease causing. The variant is novel. This is a semi-conservative amino acid change with a neutral, polar asparagine replaced with a basic polar lysine. The asparagine at position 1257 is highly conserved across species. In silico analysis (PolyPhen) predicts the variant to be possibly damaging. Variants at surrounding residues (p.Ala1255Thr, p.Gly1260Asp) have been reported in association with cardiomyopathy. In total the variant has not been seen in 5600 published controls and publicly available population datasets. There is no variation at codon 1257 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5300 Caucasian and African American individuals (as of 3/28/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 3/28/2012).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001251033	SCV001426426	likely pathogenic	Asymmetric septal hypertrophy	2018-01-01	no assertion criteria provided	research