ClinVar Miner

Submissions for variant NM_022041.3(GAN):c.1445C>T (p.Ala482Val) (rs146576740)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255353 SCV000321700 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the GAN gene. The A482V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports A482V was observed in 23/8600 (0.3%) alleles from individuals of European American background, and the 1000 Genomes Project reports it was observed in 2/182 (1.1%) alleles from individuals of British descent. The A482V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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, a missense variant in a nearby residue (E486K) has been reported in the Human Gene Mutation Database in association with GAN-related disorder (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999842 SCV000603802 uncertain significance Giant axonal neuropathy 1 2019-12-09 criteria provided, single submitter clinical testing The GAN c.1445C>T; p.Ala482Val variant (rs146576740), to our knowledge, is not reported in the medical literature, but is reported in ClinVar (Variation ID: 265171). This variant is found in the general population with an overall allele frequency of 0.17% (468/282820 alleles) in the Genome Aggregation Database. The alanine at codon 482 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ala482Val variant is uncertain at this time.
Invitae RCV000999842 SCV000640426 likely benign Giant axonal neuropathy 1 2020-12-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000755274 SCV001151027 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000999842 SCV001274788 uncertain significance Giant axonal neuropathy 1 2018-01-13 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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