ClinVar Miner

Submissions for variant NM_004737.6(LARGE1):c.1420G>A (p.Val474Ile) (rs150861748)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Inc RCV000710157 SCV000613992 uncertain significance not provided 2018-04-13 criteria provided, single submitter clinical testing
Invitae RCV000540677 SCV000638975 uncertain significance Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B6 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 474 of the LARGE11 protein (p.Val474Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs150861748, ExAC 0.1%). This variant has not been reported in the literature in individuals with LARGE11-related disease. ClinVar contains an entry for this variant (Variation ID: 95164). 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, but 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.
Fulgent Genetics,Fulgent Genetics RCV000764383 SCV000895436 uncertain significance Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B6; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1; Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A6 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001148299 SCV001309187 uncertain significance Congenital muscular dystrophy-dystroglycanopathy 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 Clinical Services Laboratory,Illumina RCV000540677 SCV001309188 uncertain significance Congenital muscular dystrophy-dystroglycanopathy with mental retardation, 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.

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