Submissions for variant NM_000053.4(ATP7B):c.3741C>G (p.His1247Gln)

gnomAD frequency: 0.00001  dbSNP: rs767464491

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664771	SCV001586747	pathogenic	Wilson disease	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1247 of the ATP7B protein (p.His1247Gln). This variant is present in population databases (rs767464491, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson disease (PMID: 31059521, 33640437). ClinVar contains an entry for this variant (Variation ID: 550125). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000664771	SCV001977541	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664771	SCV001983644	pathogenic	Wilson disease	2021-09-17	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3741C>G (p.His1247Gln) results in a non-conservative amino acid change located in the ATP binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: two predict the variant creates a cryptic 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249572 control chromosomes. c.3741C>G has been reported in the literature in multiple individuals affected with Wilson Disease (Mukherjee_2014, Dong_2016, Singh_2019, Collins_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that variant effect results in decreased serum ceruloplasmin in the patient (Singh_2019). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000664771	SCV004216320	likely pathogenic	Wilson disease	2023-09-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000664771	SCV004845300	uncertain significance	Wilson disease	2024-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 1247 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease, including in the compound heterozygous state (PMID: 24094725, 27022412, 31059521, 33640437). This variant has been identified in 2/249572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000664771	SCV005044738	pathogenic	Wilson disease		criteria provided, single submitter	clinical testing	The missense c.3741C>G p.His1247Gln variant in ATP7B gene has not been reported in homozygous and compound heterozygous state in individuals affected with Wilson Disease Singh et al. 2019; Collins CJ et al. 2021. The p.His1247Gln variant has allele frequency 0.0008% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. Experimental evidence evaluating an impact on protein function and showed that variant effect results in decreased serum ceruloplasmin in the patient Singh et al. 2019.This variant has been reported to the ClinVar database as Uncertain Significance / Likely pathogenic / Pathogenic. The amino acid change p.His1247Gln in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid His at position 1247 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS.
Mayo Clinic Laboratories, Mayo Clinic	RCV004792357	SCV005408515	uncertain significance	not provided	2024-02-14	criteria provided, single submitter	clinical testing	PM2_moderate, PM3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000664771	SCV005418495	likely pathogenic	Wilson disease		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3_Strong
Fulgent Genetics, Fulgent Genetics	RCV000664771	SCV005636634	likely pathogenic	Wilson disease	2024-03-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000664771	SCV000788782	uncertain significance	Wilson disease	2017-01-03	flagged submission	clinical testing