ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4259G>A (p.Arg1420Gln) (rs397516207)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000200190 SCV000059549 likely pathogenic Hypertrophic cardiomyopathy 2019-08-14 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000035898 SCV000208582 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing The R1420Q variant in the MYH7 gene has been reported in association with HCM (Bortot et al., 2011; Lopes et al., 2015; Murphy et al., 2016). Initially, Bortot et al. (2011) reported this variant one individual with HCM and described as segregating with disease in additional affected family members; however, detailed information was not provided. Additionally, this variant has been reported in one patient with sudden arrhythmic death syndreom (SADS) (Lahrouchi et al., 2017). The R1420Q variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals. The R1420Q variant is not observed in large population cohorts (Lek et al., 2016). The R1420Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, a missense variants in the same residue (R1420W) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000200190 SCV000253684 pathogenic Hypertrophic cardiomyopathy 2019-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1420 of the MYH7 protein (p.Arg1420Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21817903, 27247418, 26914223, 27532257, 25351510, Invitae) and in an individual with sudden cardiac death (PMID: 28449774). ClinVar contains an entry for this variant (Variation ID: 43004). 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). This variant disrupts the p.Arg1420 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 15358028, 20624503, 23283745, 27532257), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770479 SCV000901922 likely pathogenic Cardiomyopathy 2018-08-23 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000035898 SCV000927243 likely pathogenic not provided 2017-04-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000770479 SCV001351781 likely pathogenic Cardiomyopathy 2020-06-15 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1420 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 8 individuals affected with hypertrophic cardiomyopathy (PMID: 21817903, 25132132, 25351510, 26914223, 27532257, 27247418, 29764897) and one individual with sudden arrhythmic death syndrome (PMID: 28449774). A variant resulting in a different missense amino acid change in the same location is previously established as pathogenic (Clinvar Variation ID: 43003). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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