ClinVar Miner

Submissions for variant NM_001105206.3(LAMA4):c.874G>A (p.Glu292Lys) (rs781838464)

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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 RCV000243600 SCV000320455 uncertain significance Cardiovascular phenotype 2015-11-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000535001 SCV000654025 uncertain significance Dilated cardiomyopathy 1JJ 2017-05-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 285 of the LAMA4 protein (p.Glu285Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs781838464, ExAC 0.02%) but has not been reported in the literature in individuals with a LAMA4-related disease. ClinVar contains an entry for this variant (Variation ID: 264484). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786338 SCV000925115 uncertain significance not provided 2017-06-14 no assertion criteria provided provider interpretation This variant was seen in one patient with DCM. Testing was performed at Invitae. Given the weak gene-disease relationship, lack of case data, and frequency in population databases we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The LAMA4 gene has only limited evidence to associate it with cardiomyopathy. LAMA4 variants have been reported in association with DCM, however only minimal evidence is available. Knoll et al (2007) identified LAMA4 as a candidate gene after a zebrafish screen then sequenced in patients with severe DCM and found a missense variant and a nonsense variant. We have not evaluated the strength of this evidence. The variant has not been reported in any cases of cardiomyopathy (not including this patient's family). There is no case data. The variant is present in 9 of 122,929 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant is present in 1 of 7652 African individuals (MAF = 0.0065%), 7 of 55,701 European individuals (MAF = 0.0063%), and 1 of 8,601 East Asian Individuals (MAF = 0.0058%).The average coverage at that site in gnomAD is 81x.

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