Submissions for variant NM_012463.4(ATP6V0A2):c.78dup (p.Ser27fs)

gnomAD frequency: 0.00004  dbSNP: rs745590426

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000599054	SCV000339824	pathogenic	not provided	2016-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000599054	SCV000709959	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Reported previously using alternate nomenclature, c.78_79insC, in an individual with cutis laxa and inguinal hernia who also harbored a ATP6V0A2 missense variant; however, parental studies were not performed to determine the phase of these two variants (Hucthagowder et al., 2009); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 19321599)
Invitae	RCV000689436	SCV000817087	pathogenic	ALG9 congenital disorder of glycosylation	2023-06-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 286400). This premature translational stop signal has been observed in individual(s) with autosomal recessive cutis laxa type 2 (PMID: 19321599). This variant is present in population databases (rs745590426, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Ser27Glnfs*28) in the ATP6V0A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP6V0A2 are known to be pathogenic (PMID: 18157129, 19321599).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265727	SCV002548464	likely pathogenic	Cutis laxa	2022-05-13	criteria provided, single submitter	clinical testing	Variant summary: ATP6V0A2 c.78dupC (p.Ser27GlnfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.1e-05 in 235348 control chromosomes. c.78dupC has been reported in the literature as c.78_79insC in a compound heterozygous genotype with a reportedly hypomorphic allele (c.260C>T, p.P87L) in at-least one individual with Cutis Laxa - ATP6V0A2 Related, who presented with mild systemic involvement (example, Hutchadowder_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 with some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.