Submissions for variant NM_000257.4(MYH7):c.4321G>T (p.Ala1441Ser)

gnomAD frequency: 0.00001  dbSNP: rs745414245

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172044	SCV000054825	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000201892	SCV000256651	uncertain significance	Sudden unexplained death	2019-01-16	criteria provided, single submitter	research	The MYH7 Ala1441Ser variant is located within the myosin tail region of the MYH7 gene and is observed in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.000021. We detected this rare variant in a sudden unexplained death case, with no signs of cardiomyopathy found on autopsy. In silico tools SIFT, MutationTaster and PolyPhen-2 predict this variant to deleterious. No reports of this variant was found in the literature. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is rare in the general population (PM2), and multiple in silico tools predict this variant to have a deleterious affect (PP3), therefore we classify MYH7 Ala1441Ser as a variant of 'uncertain significance'.
Illumina Laboratory Services, Illumina	RCV003320133	SCV000385963	uncertain significance	Myosin storage myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000384692	SCV000385964	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000290332	SCV000385965	uncertain significance	Left ventricular noncompaction cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000345240	SCV000385966	uncertain significance	Hypertrophic cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000390901	SCV000385967	uncertain significance	Scapuloperoneal myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000313875	SCV000385968	uncertain significance	MYH7-related skeletal myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777701	SCV000913640	uncertain significance	Cardiomyopathy	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1441 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 not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 4/282828 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.
Invitae	RCV000345240	SCV001218306	uncertain significance	Hypertrophic cardiomyopathy	2023-07-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1441 of the MYH7 protein (p.Ala1441Ser). This variant is present in population databases (rs745414245, gnomAD 0.004%). 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: 191728). 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. 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.
Phosphorus, Inc.	RCV001823718	SCV002073405	uncertain significance	not specified	2022-01-14	criteria provided, single submitter	clinical testing	This missense variant results in an amino acid substitution of alanine with serine at codon 1441 of the MYH7 gene. The variant has an entry in ClinVar (191728) NM_000257.4 (MYH7): c.4321G>T (p.Ala1441Ser) and has occurred in GnomAD with a total MAF of 0.0020% and highest MAF of 0.0036% in the European population. This position is conserved. In silico functional algorithms agreed, with PolyPhen calling it benign, and SIFT tolerated. The variant has not occurred in literature associated with disease. Considering that this is a rare variant, whose impact on the protein and association with disease are unknown, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002478549	SCV002775898	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	2021-07-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000777701	SCV004821515	uncertain significance	Cardiomyopathy	2023-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1441 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 not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 4/282828 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.