ClinVar Miner

Submissions for variant NM_000257.2(MYH7):c.2788G>A (p.Glu930Lys) (rs397516171)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242427 SCV000318923 likely pathogenic Cardiovascular phenotype 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000158854 SCV000208789 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing The E930K pathogenic variant in the MYH7 gene has been previously reported in multiple individuals with HCM (Marian et al., 1995; Woo et al., 2003; Song et al., 2005; Millat et al., 2010; Zou et al., 2013; Walsh et al., 2017). It has also been shown to segregate with HCM in multiple affected relatives from multiple families, as reported by Marian et al. (1995), Song et al. (2005), a different clinical laboratory (ClinVar SCV000059477.4, Landrum et al., 2016), and observed at GeneDx. The E930K 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, likely pathogenic missense variants in nearby residues (E927K, D928N, E929K, E935K, E935V), and in the same residue (E930Q), have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. Furthermore, the E930K variant is not observed in large population cohorts (Lek et al., 2016).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035826 SCV000059477 pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-19 no assertion criteria provided clinical testing The Glu930Lys variant in MYH7 has been reported in >10 individuals with HCM from 3 families and segregated with disease in 2 affected family members (Abchee 1997, Woo 2003, Song 2005, Wang 2008). This variant was also identified by our laboratory in 3 Caucasian individuals with HCM and segregated with disease in 5 affected individuals from 2 different families. Glutamic acid (Glu) at position 930 is highly conserved in mammals and across evolutionarily distant species and the change to Lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon computational evidence, absence from controls, and segregation studies.

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