ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4321G>T (p.Ala1441Ser) (rs745414245)

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Total submissions: 10
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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 Clinical Services Laboratory,Illumina RCV000339453 SCV000385963 uncertain significance Myosin storage myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000384692 SCV000385964 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000290332 SCV000385965 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000345240 SCV000385966 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000390901 SCV000385967 uncertain significance Scapuloperoneal myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000313875 SCV000385968 uncertain significance Myopathy, distal, 1 2016-06-14 criteria provided, single submitter clinical testing
Color RCV000777701 SCV000913640 uncertain significance Cardiomyopathy 2018-04-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the LMM domain of the MYH7 protein, a C-terminal tail region that forms the thick filament backbone and interacts with other proteins. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/277166 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000345240 SCV001218306 uncertain significance Hypertrophic cardiomyopathy 2019-11-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1441 of the MYH7 protein (p.Ala1441Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs745414245, ExAC 0.001%). This variant has not been reported in the literature in individuals with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 191728). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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