Submissions for variant NM_000256.3(MYBPC3):c.3771C>A (p.Asn1257Lys) (rs730880603)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766381	SCV000208196	uncertain significance	not provided	2018-11-12	criteria provided, single submitter	clinical testing	The N1257K variant of uncertain significance in the MYBPC3 gene has been reported previously inassociation with HCM (Lopes et al., 2013; Kapplinger et al., 2014). Lopes et al. (2013) reported theN1257K variant in two individuals with HCM, however, both individuals also harbored multiplevariants in other HCM-related genes. Subsequently, the N1257K variant was identified in threeindividuals either with a diagnosis of HCM or referred for HCM genetic testing, and was considered anear-definite HCM-causative mutation" (Kapplinger et al., 2014). Taking into account both studies,the N1257K variant was absent in greater than 1,700 control individuals (Lopes et al., 2013;Kapplinger et al., 2014). In addition, this variant was not observed in approximately 6,200 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it isnot a common benign variant in these populations. Although N1257K has been identifiedindependently of other cardiogenetic variants in multiple individuals referred for cardiomyopathygenetic testing at GeneDx, segregation data is currently limited or absent for these individuals due tothe lack of clinical information provided and/or insufficient participation by informative familymembers. The N1257K variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. Moreover, this substitutionoccurs at a position that is conserved across species. As a result, in silico analysis predicts this variantis probably damaging to the protein structure/function.Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign."
Invitae	RCV000234005	SCV000284245	likely pathogenic	Hypertrophic cardiomyopathy	2018-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with lysine at codon 1257 of the MYBPC3 protein (p.Asn1257Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with known and suspected hypertrophic cardiomyopathy (HCM) (PMID: 23396983, 24510615, 24793961, 27532257, 29030401, Invitae). ClinVar contains an entry for this variant (Variation ID: 181022). 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, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that has been reported in several affected individuals and is predicted to affect protein function. For these reasons, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.
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).