Submissions for variant NM_020632.3(ATP6V0A4):c.1498A>G (p.Ser500Gly)

gnomAD frequency: 0.00048  dbSNP: rs142818468

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000359274	SCV000466909	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000893603	SCV001037554	benign	not provided	2024-01-16	criteria provided, single submitter	clinical testing
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	RCV001843515	SCV002102804	likely pathogenic	Distal Renal Tubular Acidosis, Recessive	2022-03-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000893603	SCV003805720	likely benign	not provided	2021-03-28	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488571	SCV004242059	benign	not specified	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: ATP6V0A4 c.1498A>G (p.Ser500Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 251360 control chromosomes, predominantly at a frequency of 0.016 within the South Asian subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14.31 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 South Asian origin. c.1498A>G has been reported in the literature in a homozygous individual affected with hypophosphatemic rickets including renal tubular dysfunction, without evidence of co-segregation (e.g. Marik_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Renal Tubular Acidosis, Distal, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35738466). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=2), likely benign (n=1), or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.