ClinVar Miner

Submissions for variant NM_000426.3(LAMA2):c.9145C>G (p.Gln3049Glu) (rs146525742)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767113 SCV000196848 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LAMA2 gene. The Q3049E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q3049E variant is observed in 8/66728 (1.0%) alleles from individuals of European background, (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. However, the Q3049E variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Center for Genetic Medicine Research,Children's National Medical Center RCV000227406 SCV000265822 uncertain significance not specified 2015-12-01 criteria provided, single submitter research
Counsyl RCV000674500 SCV000799846 uncertain significance Merosin deficient congenital muscular dystrophy 2018-05-10 criteria provided, single submitter clinical testing
Invitae RCV000707347 SCV000836439 uncertain significance Laminin alpha 2-related dystrophy 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 3049 of the LAMA2 protein (p.Gln3049Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs146525742, ExAC 0.01%). This variant has been reported in the heterozygous state in an individual affected with limb-girdle muscular dystrophy (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 162582). 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 glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV001154393 SCV001315749 uncertain significance Congenital muscular dystrophy due to partial LAMA2 deficiency 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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