ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2649_2651GAA[1] (p.Lys884del) (rs193922387)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617337 SCV000737352 uncertain significance Cardiovascular phenotype 2016-06-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000766940 SCV000619460 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The c.2652_2654delGAA variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified as a likely pathogenic variant in ClinVar by a different clinical laboratory (SCV000052982.1; Landrum et al., 2016), although additional evidence is not available. The c.2652_2654delGAA variant results in an in-frame, three base pair deletion, and is predicted to cause the loss of one lysine residue at position 884 in the protein, denoted p.Lys884del. This deleted residue is conserved across species and in silico analysis predicts this deletion is probably damaging to the protein structure/function. Furthermore, c.2652_2654delGAA is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity.
Integrated Genetics/Laboratory Corporation of America RCV000520629 SCV000696346 uncertain significance not specified 2018-03-01 criteria provided, single submitter clinical testing Variant summary: MYH7 c.2652_2654delGAA (p.Lys884del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 121360 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2652_2654delGAA in individuals affected with Hypertrophic or Dilated Cardiomyopathy has been reported. Furthermore, no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000535144 SCV000623676 uncertain significance Hypertrophic cardiomyopathy 2018-09-21 criteria provided, single submitter clinical testing This variant, c.2652_2654delGAA, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Lys884del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 36637). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid(s) is currently unknown. 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 RCV000535144 SCV000967721 likely pathogenic Hypertrophic cardiomyopathy 2018-10-08 criteria provided, single submitter clinical testing The p.Lys884del variant in MYH7 has been identified by other laboratories in at least 4 individuals with HCM, one of whom also had a variant in the TNNT2 gene ( GeneDx, Invitae, and Ambry personal communication; ClinVar Variation ID 36637). It was absent from large population studies. This variant is an in frame deletio n of a single amino acid at position 884. The variant falls within the head doma in of MYH7, where there is a statistically significant clustering of pathogenic variation. Furthermore, in-frame deletions of nearby amino acid residues (p.Glu8 75del, p.Lys876del, p.Glu883del) have been identified in individuals with cardio myopathy (Richard 2003, Alfares 2015, Walsh 2017), supporting that deletions in this region may generally not be tolerated. In summary, although additional stud ies are required to fully establish its clinical significance, this variant meet s criteria to be classified as likely pathogenic for autosomal dominant HCM. AC MG/AMP criteria applied: PM1, PM2, PM4, PS4_Supporting.

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