ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4283T>C (p.Leu1428Ser) (rs727503244)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618508 SCV000737035 uncertain significance Cardiovascular phenotype 2017-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000208499 SCV000264091 likely pathogenic Restrictive cardiomyopathy 2015-11-23 criteria provided, single submitter clinical testing
Color RCV000777946 SCV000914044 uncertain significance Cardiomyopathy 2018-04-19 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 have deleterious impact on 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. This variant been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 20818890, 26914223). This variant has also been identified in 11/126664 chromosomes in the general non-Finnish European population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000151240 SCV000208587 uncertain significance not specified 2017-05-26 criteria provided, single submitter clinical testing p.Leu1428Ser (TTG>TCG): c.4283 T>C in exon 31 of the MYH7 gene (NM_000257.2). A missense variant that is likely pathogenic was identified in the MYH7 gene. It has not been published as a mutation or been reported as a benign polymorphism to our knowledge, however it has been identified in other unrelated individuals tested at GeneDx. The L1428S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L1428S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, the L1428 residue, located in the myosin heavy chain, is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Lastly, Missense mutations in nearby residues (R1420W, R1420Q, E1426K, R1434C) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM,HCM panel(s).
Invitae RCV000473362 SCV000546197 uncertain significance Hypertrophic cardiomyopathy 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 1428 of the MYH7 protein (p.Leu1428Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs727503244, ExAC 0.006%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 20818890, 25611685, 26914223, 27247418, 27224906). ClinVar contains an entry for this variant (Variation ID: 164289). 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: "Probably 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151240 SCV000199117 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu1428Se r variant in MYH7 has been identified in at least 3 individuals with HCM (Ho 201 0, Homburger 2016, Murphy 2016, LMM data). This variant has also been identified in 4/67704 of European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs727503244). Leucine (Leu) at position 14 28 is highly conserved in mammals and across evolutionarily distant species and the change to serine (Ser) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction i s estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Leu 1428Ser variant is uncertain.

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