Submissions for variant NM_000257.4(MYH7):c.706G>A (p.Val236Ile)

gnomAD frequency: 0.00002  dbSNP: rs397516261

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035991	SCV000059643	uncertain significance	not specified	2020-10-05	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766756	SCV000582913	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	Reported in association with DCM (PMID: 20474083); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20474083, 27532257, 29300372)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703942	SCV000832870	uncertain significance	Hypertrophic cardiomyopathy	2025-01-22	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 236 of the MYH7 protein (p.Val236Ile). This variant is present in population databases (rs397516261, gnomAD 0.003%). This missense change has been observed in individuals with dilated cardiomyopathy and/or MYH7-related conditions (PMID: 20474083, 36264615; internal data). ClinVar contains an entry for this variant (Variation ID: 43096). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Baylor Genetics	RCV001329736	SCV001521256	uncertain significance	Dilated cardiomyopathy 1S	2019-10-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV003362670	SCV004080575	uncertain significance	Cardiovascular phenotype	2022-04-01	criteria provided, single submitter	clinical testing	The c.706G>A (p.V236I) alteration is located in exon 8 (coding exon 6) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 706, causing the valine (V) at amino acid position 236 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003996217	SCV004837787	uncertain significance	Cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 236 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 2/251494 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766756	SCV001744167	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000766756	SCV001808257	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541084	SCV004796837	uncertain significance	MYH7-related disorder	2024-02-07	no assertion criteria provided	clinical testing	The MYH7 c.706G>A variant is predicted to result in the amino acid substitution p.Val236Ile. This variant was reported in a dilated cardiomyopathy cohort (Table S2, Zimmerman et al. 2010. PubMed ID: 20474083) and a large UK biobank cohort (Table S4, Bourfiss et al. 2022. PubMed ID: 36264615). However, detailed clinical information was not available. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. A different nucleotide substitution affecting the same amino acid (p.Val236Ala) has been reported to be associated with hypertrophic cardiomyopathy (Table S1B, Walsh et al. 2017. PubMed ID: 27532257). At this time, the clinical significance of the c.706G>A (p.Val236Ile) variant is uncertain due to the absence of conclusive functional and genetic evidence.