ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5305C>A (p.Leu1769Met) (rs139222507)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001040988 SCV001204582 uncertain significance Hypertrophic cardiomyopathy 2020-04-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 1769 of the MYH7 protein (p.Leu1769Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs139222507, ExAC 0.001%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 22429680). ClinVar contains an entry for this variant (Variation ID: 161323). 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.
Color Health, Inc RCV001182017 SCV001347331 uncertain significance Cardiomyopathy 2019-11-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148702 SCV000190431 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223890 SCV000280363 likely pathogenic not provided 2014-03-26 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Including this patient’s case of DCM, this variant has been seen in 1 case of DCM and 1 case of HCM. No segregation data is available. Girolami et al (2006) found the p.Leu1769Met variant in one individual with HCM. No segregation data was reported. No other variants have been reported at codon 1769, however, variants at nearby codons (p. Ala1766Thr, p. Glu1768Lys) have been reported in association with cardiomyopathy (Klassen et al 2008, Van Driest et al 2004). This variant is predicted to be “probably damaging” by PolyPhen-2 analysis. Leucine is completely conserved across all vertebrate species at position 1769. This variant substitutes a nonpolar, neutral amino acid (Leu) with a nonpolar, neutral amino acid (Met). Girolami et al (2006) did not identify the variant in 100 presumably healthy controls (presumably from individuals of Italian ancestry). GeneDx has not observed this variant in 200 control individuals of Caucasian and African American ancestry, for a total of 300 controls.

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