Nephrocalcinosis or nephrolithiasis

Gene: ATP6V0A4

The mode of inheritance of this gene has been updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 2:21 p.m. | Last Modified: 30 Jan 2023, 2:21 p.m.

Panel Version: 3.4

Comment on mode of inheritance: Literature search showed that a single Japanese individual was reported in 2016 (PMID: 27274828) with a supposedly pathogenic heterozygous variant p.S544L. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. In 2020, a second Han Chinese family with five dRTA patients was reported (PMID: 32123165) who harboured the same p.S544L heterozygous variant. Some patients in this family were more severely affected than the previous case, displaying more severe complete dRTA with hypokalemia, osteoporosis, and kidney stones. Note this family also harboured 3 other homozygous variants in the ATP6V0A4 gene but these were ruled out, presumably due to MAF.

Apart from these two reports’ alternations in ATP6V0A4 have been found to be inherited recessively (heterozygous parent carriers are unaffected), and multiple such cases have been described in literature (references added to publications list).

At this moment there is only enough evidence to support an Amber rating for the monoallelic form - single heterozygous variant identified in 2 families from a similar ethnic background which does not suffice the inclusion criteria.

MOI should be changed from 'BOTH mono- and biallelic' to 'BIALLELIC' only at the next GMS panel review (tagged) until additional evidence emerges supporting heterozygous variants as disease-causing.

Created: 16 Jul 2021, 2:50 p.m. | Last Modified: 16 Jul 2021, 2:50 p.m.

Panel Version: 2.20

The majority of cases report biallelic inheritance of variants in ATP6V0A4 in association with Renal tubular acidosis, distal, autosomal recessive. However, PMID: 27274828 - Imai et al 2016 - report a 40-year-old Japanese man in which hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. A novel heterozygous mutation in the ATP6V0A4 gene encoding the vacuolar H(+)-ATPase (V-ATPase) a4 subunit p.S544L was detected.

Created: 6 Nov 2019, 4:58 p.m. | Last Modified: 6 Nov 2019, 4:58 p.m.

Panel Version: 1.43

Comment on list classification: Promoted from red to green due to expert review, and evidence in OMIM.

Created: 20 May 2016, 9:09 a.m.

Green List (high evidence)

See 'dRTA' category

Created: 29 Oct 2015, 10:43 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Compensated or uncomensated dRTA and/or recurrent stone formation, usually with hypocitraturia. +/- deafness