Submissions for variant NM_000256.3(MYBPC3):c.3751T>C (p.Tyr1251His)

dbSNP: rs730880601

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766379	SCV000208192	uncertain significance	not provided	2017-03-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The Y1251H variant has been reported as a rare variant in one individual from an HCM-affected cohort (Lopes et al. 2015); however, additional clinical information, segregation data and functional studies were not provided. Nevertheless, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y1251H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223863	SCV000712389	uncertain significance	not specified	2016-07-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr1251Hi s variant in MYBPC3 has not been previously reported in individuals with cardiom yopathy or in large population studies. Tyrosine (Tyr) at position 1251 is highl y conserved in mammals and across evolutionarily distant species and the change to Histidine (His) was predicted to be pathogenic using a computational tool cli nically validated by our laboratory. This tool's pathogenic prediction is estima ted to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr1251His variant is uncertain.
Invitae	RCV001850212	SCV002284152	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1251 of the MYBPC3 protein (p.Tyr1251His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25351510, 33782553, 36578016). ClinVar contains an entry for this variant (Variation ID: 181020). 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. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 34097875). 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.
Ambry Genetics	RCV002345532	SCV002621278	uncertain significance	Cardiovascular phenotype	2020-12-15	criteria provided, single submitter	clinical testing	The p.Y1251H variant (also known as c.3751T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 3751. The tyrosine at codon 1251 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223863	SCV000280268	uncertain significance	not specified	2011-11-17	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. p.Tyr1251His (c.3751 T>C) in MYBPC3 Based on the data reviewed below, we consider it a variant of uncertain significance. The variant is novel. It has not been reported previously in association with disease. This is a semi-conservative amino acid substitution, where a neutral, polar Tyrosine residue is exchanged for a positively charged Histidine residue. The Tyrosine at this position is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging, and Mutation Taster predicts the variant to be disease-causing in all three transcripts. Other variants have been reported in association with disease at nearby codons (p.Pro1245Leu, p.Gly1248Arg, p.Ala1255Thr). Legacy names for this variant include Tyr903 and Tyr1250, none of which have any associated literature. In total the variant has not been seen in 6500 published controls and publicly available population datasets. There is no variation at codon 1251 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of May 16, 2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of May 16, 2013).