ClinVar Miner

Submissions for variant NM_001105206.3(LAMA4):c.307C>T (p.Arg103Trp) (rs138176093)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482041 SCV000570414 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LAMA4 gene. The R103W variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 17/66,690 (0.025%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). Nevertheless, the R103W 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. Finally, this substitution occurs at a position that is conserved across species and in silico analysis suggests that this variant is probably damaging to the protein structure/function.
Ambry Genetics RCV000617622 SCV000735829 uncertain significance Cardiovascular phenotype 2017-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000686153 SCV000813657 uncertain significance Dilated cardiomyopathy 1JJ 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 103 of the LAMA4 protein (p.Arg103Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs138176093, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with LAMA4-related disease. ClinVar contains an entry for this variant (Variation ID: 421269). 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: "Benign"; 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.

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