Nephrocalcinosis or nephrolithiasis

Gene: ATP6V1B1

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

Created: 10 Dec 2025, 3:14 p.m. | Last Modified: 10 Dec 2025, 3:14 p.m.

Panel Version: 5.4

Green List (high evidence)

Using a retrospective analysis of twenty index patients with distal renal tubular acidosis (OMIM:267300), Daenen et al (PMID: 39837581) report heterozygous ATP6V1B1(NM_001692.4):c.1181G>A, p.(Arg394Gln) in 19 cases and one case who was heterozygous for ATP6V1B1(NM_001692.4): c.1180C>G; p.(Arg394Gly) from seven families, in contrast to the previously reported biallelic ATP6V1B1 associated with OMIM:267300 (PMID: 9916796; 12566520; 18798332). The variants segregate with the condition in six of the families, in the remaining family (family D) the unaffected mother is mosaic for the ATP6V1B1(NM_001692.4):c.1181G>A, p.(Arg394Gln) and her two sons are heterozygous for the variant (figure 1, PMID: 39837581).

The acidosis associated with the heterozygous ATP6V1B1 p. Arg394 variants appears to be similar to that in the homozygous cases previously reported (PMID: 9916796; 12566520; 18798332). However, the sensorineural hearing loss was milder or absent from the heterozygous cohort (PMID: 39837581).

Using structural modelling, Daenen et al suggest that a dominant negative disease mechanism could be responsible for the effect of the heterozygous ATP6V1B1 p. Arg394 variants (PMID: 39837581).

Created: 7 Apr 2025, 3:35 p.m. | Last Modified: 7 Apr 2025, 3:35 p.m.

Panel Version: 4.20

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, OMIM:267300; renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss, MONDO:0009968

Publications

• 39837581
• 9916796
• 12566520
• 18798332

Green List (high evidence)

Strong evidence for the pathogenicity of heterozygous variants affecting ATP6V1B1 Arg394 and thus a novel inheritance modus for ATP6V1B1-associated dRTA. The mode of inheritance can therefore be considered BOTH monoallelic and biallelic. The prominent position of Arg394 in the nucleotide binding fold of the H+-ATPase structure is consistent with a dominant negative mechanism. (PMID 39837581)

Created: 17 Feb 2025, 5:32 p.m. | Last Modified: 17 Feb 2025, 5:32 p.m.

Panel Version: 4.19

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• PMID 39837581

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: Can include renal stones, primarily a renal tubular acidosis gene.

Created: 23 May 2016, 12:30 p.m.