Submissions for variant NM_005765.3(ATP6AP2):c.858G>A (p.Ala286=)

dbSNP: rs1555978069

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640919	SCV000762523	uncertain significance	Syndromic X-linked intellectual disability Hedera type	2017-10-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 286 of the ATP6AP2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATP6AP2 protein. This variant also falls at the last nucleotide of exon 8 of the ATP6AP2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATP6AP2-related disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000640919	SCV001934408	uncertain significance	Syndromic X-linked intellectual disability Hedera type	2021-02-01	criteria provided, single submitter	clinical testing	Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015)
Ambry Genetics	RCV004025614	SCV004913539	uncertain significance	Inborn genetic diseases	2021-09-14	criteria provided, single submitter	clinical testing	The c.858G>A (p.A286A) alteration is located in exon 8 (coding exon 8) of the ATP6AP2 gene. This alteration consists of a G to A substitution at nucleotide position 858. This nucleotide substitution does not change the alanine (A) at codon 286. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796259	SCV005418859	uncertain significance	Syndromic X-linked intellectual disability Hedera type; X-linked parkinsonism-spasticity syndrome; Congenital disorder of glycosylation, type IIr		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PS2_Moderate+PP4
CeGaT Center for Human Genetics Tuebingen	RCV004808817	SCV005433032	uncertain significance	not provided	2024-09-01	criteria provided, single submitter	clinical testing	ATP6AP2: PS2:Moderate, PM2:Supporting, BP4