Submissions for variant NM_000257.4(MYH7):c.1049A>G (p.Tyr350Cys)

dbSNP: rs876661150

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217277	SCV000279670	uncertain significance	not provided	2017-05-23	criteria provided, single submitter	clinical testing	The Y350C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different missense variant at the same residue (Y350N) has been reported as a de novo variant in a 26 year-old female with Ebstein anomaly and biventricular noncompaction, and was absent from more than 980 control chromosomes (Postma A et al., 2011). The Y350C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y350C 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. 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. Furthermore, missense variants in nearby residues (M349T, K351E, A355T) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae	RCV001854741	SCV002160584	pathogenic	Hypertrophic cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr350 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21127202, 34540771). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 234667). This missense change has been observed in individual(s) with left ventricular noncompaction (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 350 of the MYH7 protein (p.Tyr350Cys).
Clinical Genetics, Academic Medical Center	RCV000217277	SCV001921781	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000217277	SCV001971438	uncertain significance	not provided		no assertion criteria provided	clinical testing