ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4399C>G (p.Leu1467Val) (rs397516214)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158865 SCV000208800 likely pathogenic not provided 2011-10-18 criteria provided, single submitter clinical testing This missense change is denoted Leu1467Val (aka L1467V) at the protein level and c.4399 C>G at the cDNA level. The Leu1467Val variant in the MYH7 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Although Leu1467Val results in a conservative amino acid substitution of one non-polar amino acid with another, it occurs at a position that is highly conserved throughout evolution. In silico analysis predicts Leu1467Val to be damaging to the protein structure/function. In addition, mutations in nearby codons (Ala1454Thr, Lys1459Asn, Arg1475Cys) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, Leu1467Val was not observed in 696 control alleles from individuals of various ethnic backgrounds tested at GeneDx, indicating it is not a common benign polymorphism. With the clinical and molecular information available at this time, we cannot unequivocally determine the clinical significance of Leu1467Val, although evidence suggests it is likely disease-causing. The variant is found in DCM,HCM panel(s).
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770478 SCV000901921 uncertain significance Cardiomyopathy 2018-12-20 criteria provided, single submitter clinical testing
Mendelics RCV000989186 SCV001139409 uncertain significance Familial hypertrophic cardiomyopathy 1 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000770478 SCV001357323 uncertain significance Cardiomyopathy 2021-02-22 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 1467 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with multi-minicore disease and cardiomyopathy, who had a family history of early death presumed to be of cardiac origin (PMID: 22784669). This variant has also been identified in 34/251430 chromosomes (34/30616 chromosomes in South Asian) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for MYH7-related disorders, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035909 SCV001360974 uncertain significance not specified 2019-04-08 criteria provided, single submitter clinical testing Variant summary: MYH7 c.4399C>G (p.Leu1467Val) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 246202 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Hypertrophic Cardiomyopathy (0.00014 vs 0.001), allowing no conclusion about variant significance. c.4399C>G has been reported in the literature in individuals affected with DCM, HCM, or multi-minicore disease with cardiac involvement (Lakdawala_2012, Cullup_2012, Pugh_2014, Viswanathan_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001223389 SCV001395536 uncertain significance Hypertrophic cardiomyopathy 2019-08-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1467 of the MYH7 protein (p.Leu1467Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs397516214, ExAC 0.1%). This variant has been observed in individuals with clinical features of multi-minicore disease or hypertrophic cardiomyopathy (PMID: 22784669, 29121657). ClinVar contains an entry for this variant (Variation ID: 43015). 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 RCV000035909 SCV000059560 uncertain significance not specified 2014-01-17 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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