Submissions for variant NM_000257.4(MYH7):c.969T>G (p.Ile323Met)

gnomAD frequency: 0.00001  dbSNP: rs730880861

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766415	SCV000208711	uncertain significance	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 27532257, 29300372)
Invitae	RCV000817033	SCV000957569	uncertain significance	Hypertrophic cardiomyopathy	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 323 of the MYH7 protein (p.Ile323Met). This variant is present in population databases (rs730880861, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181332). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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	RCV001185246	SCV001351419	uncertain significance	Cardiomyopathy	2019-11-04	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 323 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251326 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	RCV002484985	SCV002787947	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	2021-09-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001185246	SCV004830331	uncertain significance	Cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158776	SCV000280382	uncertain significance	not specified	2012-05-30	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.Ile323Met (I323M;c.969 T>G) in the MYH7 gene This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. Variation at nearby residues in MYH7 has been associated with cardiomyopathy, supporting the functional importance of this region of the protein: Val320Met, Ser322Phe, Ala326Pro (HGMD via GeneDx). This is a conservative amino acid change from a nonpolar isoleucine to a nonpolar methionine. The isoleucine at codon 323 is conserved across species, according to GeneDx. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging” with a score of 0.475. In total this variant has not been seen in ~6500 individuals from published controls and publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however. (Our patient has Mexican ancestry.) No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). No variation at this codon is present in dbSNP or in 1000 genomes. 1000 genomes contains 66 individuals of Mexican ancestry from Los Angeles, as of January 8, 2013. (Out of 1092 genotypes in phase 1, there are 66 people of Mexican ancestry from LA, 55 Puerto Ricans, 60 Colombians from Medellin, totaling 181 individuals.) GeneDx did not report controls.