Submissions for variant NM_000257.4(MYH7):c.2692C>G (p.Leu898Val)

dbSNP: rs727504407

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154590	SCV000204263	uncertain significance	not specified	2016-02-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu898Val variant in MYH7 has been identified by our laboratory in 1 Caucasian individual HCM, and was absent from large population studies. This variant was predicted t o be pathogenic using a computational tool clinically validated by our laborator y. This tool's pathogenic prediction is estimated 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.Leu898Val variant is uncertain.
GeneDx	RCV000154590	SCV000208495	uncertain significance	not specified	2016-11-30	criteria provided, single submitter	clinical testing	The Leu898Val variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Leu898Val results in a conservative amino acid substitution of one non-polar amino acid with another, it occurs at a residue that is conserved across species. In silico analysis predicts Leu898Val is probably damaging to the protein structure/function. Mutations in nearby residues (Glu894Gly, Ala901Pro, Ala901Gly, Glu903Lys, Glu903Gly) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the Leu898Val 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. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in HCM panel(s).
Invitae	RCV001850117	SCV002178560	uncertain significance	Hypertrophic cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 898 of the MYH7 protein (p.Leu898Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 32746448; Invitae). ClinVar contains an entry for this variant (Variation ID: 177930). 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. 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.