Submissions for variant NM_000257.4(MYH7):c.4835T>C (p.Leu1612Pro)

dbSNP: rs587779392

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459843	SCV000546201	likely pathogenic	Hypertrophic cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. 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: 143213). This missense change has been observed in individuals with clinical features of autosomal dominant MYH7-related conditions (PMID: 24664454; Invitae). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1612 of the MYH7 protein (p.Leu1612Pro).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002515923	SCV003761217	likely pathogenic	Qualitative or quantitative defects of beta-myosin heavy chain (MYH7)	2023-01-24	criteria provided, single submitter	curation	The heterozygous p.Leu1612Pro variant in MYH7 was identified by our study in one individual with multiminicore myopathy and aortic aneurysm. The p.Leu1612Pro variant in MYH7 has been reported in one individual with Laing early distal myopathy (MPDI) (PMID: 24664454). This variant was assumed de novo in this one individual, but maternity and paternity have not been confirmed (PMID: 24664454). This variant has also been reported in ClinVar (Variation ID:143213) and has been interpreted as pathogenic by Royal Perth Hospital Neurogenetics Laboratory and as a variant of uncertain significance (VUS) by Invitae. This variant was absent from large population studies. The number of missense variants reported in MYH7 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Multiple variants in the same region as p.Leu1612Pro variant have been reported in association with disease in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity ( PMID: 24664454). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant MYH7-associated myopathy. ACMG/AMP Criteria applied: PS4_Supporting, PM1, PM2_Supporting, PM6_Supporting, PP3 (Richards 2015).
Neurogenetics Laboratory, Royal Perth Hospital	RCV000132752	SCV000119903	pathogenic	MYH7-related skeletal myopathy	2013-01-01	no assertion criteria provided	clinical testing