ClinVar Miner

Submissions for variant NM_001105206.3(LAMA4):c.4583G>A (p.Arg1528His) (rs782805733)

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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 RCV000621022 SCV000737148 uncertain significance Cardiovascular phenotype 2016-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000198503 SCV000250560 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing p.Arg1521His (CGC>CAC): c.4562 G>A in exon 33 of the LAMA4 gene (NM_002290.3). A variant of unknown significance has been identified in the LAMA4 gene. The R1521H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1521H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved within mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, the R1521H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in CARDIOMYOPATHY
Invitae RCV000651437 SCV000773288 uncertain significance Dilated cardiomyopathy 1JJ 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1521 of the LAMA4 protein (p.Arg1521His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs782805733, ExAC 0.006%). This variant has not been reported in the literature in individuals with LAMA4-related disease. ClinVar contains an entry for this variant (Variation ID: 213607). 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: "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.

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