Submissions for variant NM_000053.4(ATP7B):c.3426G>C (p.Gln1142His)

gnomAD frequency: 0.00003  dbSNP: rs778749563

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409630	SCV000485394	likely pathogenic	Wilson disease	2015-12-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409630	SCV000934021	uncertain significance	Wilson disease	2020-03-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with histidine at codon 1142 of the ATP7B protein (p.Gln1142His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs778749563, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Wilson disease (PMID: 11405812). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. It has also been reported in other unrelated affected individuals (PMID: 26483271, 11043508, 9829905) although in some of these individuals another variant was identified in the same allele. ClinVar contains an entry for this variant (Variation ID: 370151). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Genome-Nilou Lab	RCV000409630	SCV001977554	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469139	SCV002766260	uncertain significance	not specified	2023-09-28	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3426G>C (p.Gln1142His) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249588 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3426G>C has been reported in the literature in individuals, particularly of Eastern Asian descent, affected with Wilson Disease; however, a lot of the studies (especially recent ones with comprehensively genotyped patients), report the variant to co-occur in cis with the known pathogenic variant c.3443T>C (p.Ile1148Thr) (e.g. Tsai_1998, Lee_200, Wu_2001, Wu_2003, Mak_2008, Wang_2011, Coffey_2013, Dong_2016, Poon_2016, Hou_2022, Li_2021_Zhang_2022). In support of this observation, control data indicate these two variants are likely found on the same haplotype in most individuals in gnomAD. These data do not allow any conclusion about the significance of the p.Gln1142His variant on its own. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23518715, 27022412, 35079019, 11043508, 18034201, 26483271, 9829905, 21796144, 11405812, 12756138, 34470610, 35220961). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.