ClinVar Miner

Submissions for variant NM_020632.3(ATP6V0A4):c.419C>T (p.Thr140Met)

gnomAD frequency: 0.00065  dbSNP: rs144802156
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000342844 SCV000466923 uncertain significance Autosomal recessive distal renal tubular acidosis 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797709 SCV002041762 uncertain significance not specified 2023-12-07 criteria provided, single submitter clinical testing Variant summary: ATP6V0A4 c.419C>T (p.Thr140Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 1,607,008 control chromosomes (i.e. in 279 carriers), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database (v4.0 dataset). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP6V0A4 causing Renal Tubular Acidosis, Distal, Autosomal Recessive phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.419C>T has been reported in the literature as a heterozygous genotype along with another heterozygous variant in the ATP6V1B1 gene (c.437A>G, p.Asp146Gly) in an individual of Libyan (North African) ancestry affected with Distal Renal Tubular Acidosis. The authors proposed a possible digenic model of inheritance. These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Distal Renal Tubular Acidosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29024829). Another submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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