ClinVar Miner

Submissions for variant NM_001105206.3(LAMA4):c.3817T>C (p.Phe1273Leu)

gnomAD frequency: 0.00009  dbSNP: rs781966924
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757428 SCV000885645 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing The p.Phe1266Leu variant (rs781966924) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.006 percent (identified on 7 out of 120258 chromosomes). The phenylalanine at position 1266 is highly conserved (Alamut v2.9.0) and computational analyses of the effects of the p.Phe1266Leu variant on protein structure and function indicates neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Phe1266Leu variant with certainty.
Invitae RCV001855892 SCV002254517 uncertain significance Dilated cardiomyopathy 1JJ 2022-04-25 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs781966924, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1266 of the LAMA4 protein (p.Phe1266Leu). ClinVar contains an entry for this variant (Variation ID: 618698). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV002352265 SCV002622716 uncertain significance Cardiovascular phenotype 2021-03-30 criteria provided, single submitter clinical testing The p.F1266L variant (also known as c.3796T>C), located in coding exon 27 of the LAMA4 gene, results from a T to C substitution at nucleotide position 3796. The phenylalanine at codon 1266 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003965566 SCV004783353 likely benign LAMA4-related condition 2022-07-08 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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