Submissions for variant NM_000256.3(MYBPC3):c.2539T>C (p.Tyr847His)

dbSNP: rs768963157

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489291	SCV000577777	uncertain significance	not provided	2018-02-14	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. This variant has been reported in association with HCM in an individual, identified to have a second pathogenic variant (Liu W et al., 2013). Liu et al. (2013) observed that this individuals has features of HCM consistent with compound heterozygosity, however there is lack of functional and segregation data for this variant. The Y847H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Y847H 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.In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nonetheless, additional evidence is needed to clarify pathogenicity, including significant observation in affected individuals, informative segregation data, and functional evidence.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816056	SCV000956545	uncertain significance	Hypertrophic cardiomyopathy	2024-04-04	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 847 of the MYBPC3 protein (p.Tyr847His). This variant is present in population databases (rs768963157, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20021930). ClinVar contains an entry for this variant (Variation ID: 427144). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002455953	SCV002739327	uncertain significance	Cardiovascular phenotype	2021-04-06	criteria provided, single submitter	clinical testing	The p.Y847H variant (also known as c.2539T>C), located in coding exon 25 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 2539. The tyrosine at codon 847 is replaced by histidine, an amino acid with similar properties. This variant co-occurred with a second MYBPC3 variant in an individual with hypertrophic cardiomyopathy (Liu W et al. Am J Cardiol, 2013 Aug;112:585-9). 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.