Submissions for variant NM_133642.5(LARGE1):c.1420G>A (p.Val474Ile)

gnomAD frequency: 0.00119  dbSNP: rs150861748

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710157	SCV000113078	uncertain significance	not provided	2013-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000192984	SCV000196856	uncertain significance	not specified	2017-08-17	criteria provided, single submitter	clinical testing	The V474I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V474I variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species within the predicted lumenal domain of the LARGE protein. However, the V474I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LARGE panel.
Genetic Services Laboratory, University of Chicago	RCV000192984	SCV000247832	uncertain significance	not specified	2015-07-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710157	SCV000613992	uncertain significance	not provided	2018-04-13	criteria provided, single submitter	clinical testing
Invitae	RCV000540677	SCV000638975	uncertain significance	Muscular dystrophy-dystroglycanopathy type B6	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 474 of the LARGE1 protein (p.Val474Ile). This variant is present in population databases (rs150861748, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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: 95164). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LARGE1 protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000764383	SCV000895436	uncertain significance	Muscular dystrophy-dystroglycanopathy type B6; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6	2022-04-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001148299	SCV001309187	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000540677	SCV001309188	uncertain significance	Muscular dystrophy-dystroglycanopathy type B6	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000710157	SCV001715617	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing	BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710157	SCV002048773	uncertain significance	not provided	2021-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925066	SCV004738537	likely benign	LARGE1-related disorder	2023-06-26	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).