ClinVar Miner

Submissions for variant NM_001698.3(AUH):c.381A>G (rs146227896)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200381 SCV000251186 uncertain significance not specified 2017-04-19 criteria provided, single submitter clinical testing p.Ile127Met (ATA>ATG):c.381 A>G in exon 3 of the AUH gene (NM_001698.2). The I127M missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is conservative in that both Isoleucine and Methionine are uncharged, non-polar amino acids. This change occurs at a position in the AUH protein that is conserved in mammals. Multiple in-silico analysis models predict that I127M is damaging to the AUH protein. Therefore, based on the currently available information, it is unclear whether I127M is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000275240 SCV000480873 uncertain significance 3-Methylglutaconic aciduria type 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487826 SCV000575581 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Invitae RCV000275240 SCV001014469 likely benign 3-Methylglutaconic aciduria type 1 2020-11-28 criteria provided, single submitter clinical testing
Elsea Laboratory,Baylor College of Medicine RCV000275240 SCV001424186 uncertain significance 3-Methylglutaconic aciduria type 1 2020-04-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000487826 SCV001554200 likely benign not provided no assertion criteria provided clinical testing The AUH p.I127M variant was not identified in the literature but was identified in dbSNP (ID: rs146227896) and ClinVar (classified as uncertain significance by GeneDx, Illumina, CeGaT Praxis and Elsea Laboratory, Baylor College of Medicine; and as likely benign by Invitae). The variant was identified in control databases in 518 of 282744 chromosomes (5 homozygous) at a frequency of 0.001832 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I127 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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