Submissions for variant NM_020632.3(ATP6V0A4):c.1231G>T (p.Asp411Tyr)

gnomAD frequency: 0.00002  dbSNP: rs763982675

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442300	SCV000525096	likely pathogenic	not provided	2023-06-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26208211, 27247958, 35368817, 31738409)
Fulgent Genetics, Fulgent Genetics	RCV002480305	SCV000893750	pathogenic	Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss	2022-02-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000763163	SCV000916195	likely pathogenic	Autosomal recessive distal renal tubular acidosis	2018-10-26	criteria provided, single submitter	clinical testing	The ATP6V0A4 c.1231G>T (p.Asp411Tyr) variant has been described in two studies in which it was found in a total of six patiens with distal renal tubular acidosis from five families, including four in a homozygous state and two in a compound heterozygous state (Pereira et al. 2015; Escobar et al. 2016). The Asp411 residue is highly conserved. Control data are unavailable for this variant, which is reported at a frequency of 0.00061 in the Latino population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp411Tyr variant is classified as likely pathogenic for recessive distal renal tubular acidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000442300	SCV001389382	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 411 of the ATP6V0A4 protein (p.Asp411Tyr). This variant is present in population databases (rs763982675, gnomAD 0.04%). This missense change has been observed in individual(s) with renal tubular acidosis (PMID: 26208211, 27247958). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 384333). 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 expected to disrupt ATP6V0A4 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000763163	SCV002556262	pathogenic	Autosomal recessive distal renal tubular acidosis	2022-06-02	criteria provided, single submitter	clinical testing	Variant summary: ATP6V0A4 c.1231G>T (p.Asp411Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251452 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP6V0A4 causing Renal Tubular Acidosis, Distal, Autosomal Recessive (8e-05 vs 0.0011), allowing no conclusion about variant significance. c.1231G>T has been reported in the literature in multiple individuals affected with Renal Tubular Acidosis, Distal, Autosomal Recessive (example, Escobar_2016, Pereira_2015, Mansilla_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003409596	SCV004115542	pathogenic	ATP6V0A4-related condition	2023-04-20	criteria provided, single submitter	clinical testing	The ATP6V0A4 c.1231G>T variant is predicted to result in the amino acid substitution p.Asp411Tyr. This variant has been reported to be pathogenic for distal renal tubular acidosis (dRTA) (Escobar et al. 2016. PubMed ID: 27247958; reported as c.1232G>T in Pereira et al. 2015. PubMed ID: 26208211). Escobar et al. suggested this is a founder variant in individuals of Mexican ancestry. This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-138432259-C-A). This variant is interpreted as pathogenic.