ClinVar Miner

Submissions for variant NM_000227.5(LAMA3):c.3001C>T (p.Arg1001Ter) (rs768415785)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671162 SCV000796112 likely pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2017-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778526 SCV000914809 uncertain significance LAMA3-Related Disorders 2018-10-10 criteria provided, single submitter clinical testing This variant is a stop-gained variant, which was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000671162 SCV001362888 pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2019-11-04 criteria provided, single submitter clinical testing Variant summary: LAMA3 c.3001C>T (p.Arg1001X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At-least one splice variant downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.3001C>T has been reported in the literature in compound heterozygosity with another truncating alteration in at-least one individual affected with Herlitz Junctional Epidermolysis Bullosa (hemidesmosomal variants of EB (HEB), Varki_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and another classified the variant as uncertain significance. Based on the well established etiology of loss of function variants in the pathophysiology of JEB and the evidence outlined above, the variant was classified as pathogenic.

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