Submissions for variant NM_000257.4(MYH7):c.4078G>A (p.Val1360Ile)

gnomAD frequency: 0.00002  dbSNP: rs373231077

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035885	SCV000059536	uncertain significance	not specified	2019-08-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val1360Ile variant in MYH7 has been identified in 4 individuals with HCM (Wang 2014, Homburger 2016, LMM data). It has also been identified in 8/129146 European chromosomes by gnomAD and reported in ClinVar (Variation ID #42991). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062732	SCV001227549	uncertain significance	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1360 of the MYH7 protein (p.Val1360Ile). This variant is present in population databases (rs373231077, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25132132, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 42991). 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 not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001188109	SCV001355081	uncertain significance	Cardiomyopathy	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1360 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, 27247418, 27532257). This variant has been identified in 10/282832 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002490489	SCV002789134	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-11-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003129765	SCV003817740	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001188109	SCV004814384	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1360 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, 27247418, 27532257). This variant has been identified in 10/282832 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004018779	SCV005033926	likely benign	Cardiovascular phenotype	2024-02-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035885	SCV000280346	uncertain significance	not specified	2014-01-31	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.Val1360Ile (c.4078G>A) in MYH7 This is a novel variant. We classify it as a variant of uncertain significance This variant has not been described in published literature to date (as of October 2nd, 2012). Conservation analysis indicates that Valine is not highly conserved at position 1360 across species and isoforms. In total the variant has been seen in 1/6577 published controls and publicly available population datasets. The variant was recently reported online in 1 of ~4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of October 2nd, 2012). The phenotype of that individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Note that other very likely disease causing sarcomere variants have been seen in this sample at this frequency. GeneDx reports the variant is absent in 274 presumably healthy individuals.