Submissions for variant NM_000257.4(MYH7):c.4219G>A (p.Val1407Ile)

gnomAD frequency: 0.00001  dbSNP: rs730880795

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158644	SCV000208579	uncertain significance	not provided	2018-01-12	criteria provided, single submitter	clinical testing	p.Val1407Ile (GTT>ATT): c.4219 G>A in exon 31 of the MYH7 gene (NM_000257.2). A variant of unknown significance has been identified in the MYH7 gene. The V1407I variant has not been published as a mutation or as a benign polymorphism to our knowledge. The V1407I 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. In addition, this substitution occurs at a position that is completely conserved in mammals. Moreover, a missense mutation in a nearby residue L1414M has been reported in association with HCM, supporting the functional importance of this region of the protein. Nevertheless, the V1407I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV000822740	SCV000963556	uncertain significance	Hypertrophic cardiomyopathy	2023-11-28	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 1407 of the MYH7 protein (p.Val1407Ile). This variant is present in population databases (rs730880795, gnomAD 0.003%). 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: 181249). 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 with a positive 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	RCV001180569	SCV001345527	uncertain significance	Cardiomyopathy	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1407 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 33495597). This variant has been identified in 5/282872 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	RCV002484976	SCV002793207	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	2021-10-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001180569	SCV004823361	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1407 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. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 33495597). This variant has been identified in 5/282872 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	RCV004649077	SCV005143051	uncertain significance	Cardiovascular phenotype	2024-03-28	criteria provided, single submitter	clinical testing	The p.V1407I variant (also known as c.4219G>A), located in coding exon 29 of the MYH7 gene, results from a G to A substitution at nucleotide position 4219. The valine at codon 1407 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.