Renal tubulopathies

Gene: ATP6V1B1

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 heterozygous variants segregate with the condition in six of the families, in the remaining family (family D) the unaffected mother was mosaic for the ATP6V1B1(NM_001692.4):c.1181G>A, p.(Arg394Gln) and her two sons were 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, 3:50 p.m. | Last Modified: 7 Apr 2025, 3:50 p.m.

Panel Version: 4.21

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, 5:33 p.m. | Last Modified: 17 Feb 2025, 5:33 p.m.

Panel Version: 4.21

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

Green List (high evidence)

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, 2:43 p.m. | Last Modified: 10 Dec 2025, 2:43 p.m.

Panel Version: 5.10

This gene was part of an initial gene list collated by Emma Ashton (NE Thames Regional Genetics laboratory, GOSH NHS Foundation Trust) January 2019 on behalf of the GMS Renal Specialist Test Group; Gene Symbol submitted: ATP6V1B1; Suggested initial gene rating: green; Evidence for inclusion: none provided; Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none provided

Created: 3 Feb 2019, 11:32 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Renal tubular acidosis with deafness MIM 267300

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

Comment when marking as ready: Known expert and OMIM all in agreement

Created: 10 May 2016, 10:10 a.m.

Green List (high evidence)

Recent Moe paper implicates carriage of E161K in compensated dRTA and recurrent stone formation

Created: 28 Oct 2015, 7:36 p.m.

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

Both Illumina and expert sources suggest a recessive mode of inheritance.

Created: 8 Jul 2015, 1:22 p.m.