rs730880603
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000256.3(MYBPC3):c.3771C>A(p.Asn1257Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1257S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.3771C>A | p.Asn1257Lys | missense_variant | 33/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3771C>A | p.Asn1257Lys | missense_variant | 33/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.3771C>A | p.Asn1257Lys | missense_variant | 32/34 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 01, 2013 | 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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 26, 2016 | 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2022 | 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; Published functional studies suggest a damaging effect in HEK293A cells (Helms et al., 2020); This variant is associated with the following publications: (PMID: 23396983, 24510615, 24793961, 27532257, 12818575, 25351510, 29030401, 33782553, 32841044) - |
Primary familial dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | 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; Invitae). 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. - |
Asymmetric septal hypertrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 08, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at