Submissions for variant NM_133642.5(LARGE1):c.26G>A (p.Arg9Gln)

gnomAD frequency: 0.00004  dbSNP: rs763697782

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000792829	SCV000438186	uncertain significance	Muscular dystrophy-dystroglycanopathy type B6	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.
Illumina Laboratory Services, Illumina	RCV000371003	SCV000438187	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6	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.
Genetic Services Laboratory, University of Chicago	RCV000501075	SCV000595565	uncertain significance	not specified	2015-09-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792829	SCV000932150	uncertain significance	Muscular dystrophy-dystroglycanopathy type B6	2022-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 9 of the LARGE1 protein (p.Arg9Gln). This variant is present in population databases (rs763697782, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LARGE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 341439). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV002487504	SCV002775010	uncertain significance	not provided	2022-12-17	criteria provided, single submitter	clinical testing