Submissions for variant NM_000053.4(ATP7B):c.3452G>A (p.Arg1151His)

dbSNP: rs377297166

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586771	SCV000694447	uncertain significance	not provided	2016-08-30	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.3452G>A (p.Arg1151His) variant involves the alteration of a conserved nucleotide and this variant is located in the P-type ATPase and/or cytoplasmic domain N which is critical for ATP binding. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120874 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant has been reported in at least 3 WD patients (Loudianos_1999, Li_2011, Dong_2016), one was mentioned to be compound heterozygotes of this variant and Gly1089Glu. One internal sample carries this variant and a pathogenic variant (p.His1069Gln); clinical status as well as phase of the variants unknown. One in vitro study showed that this variant mildly affects the structure and ATP-binding activity of ATP7B protein using N-domain fragment (Morgan_2004). In addition, one reputable database classified this variant as disease variant. Taken together, this variant is classified as VUS-possibly pathogenic.
Invitae	RCV000666672	SCV002292010	likely pathogenic	Wilson disease	2023-02-11	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt ATP7B protein function. Experimental studies have shown that this missense change affects ATP7B function (PMID: 15205462). This variant disrupts the p.Arg1151 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17949296, 21645214, 23333878, 27398169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1151 of the ATP7B protein (p.Arg1151His). This variant is present in population databases (rs377297166, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 30655162). ClinVar contains an entry for this variant (Variation ID: 495415).
Baylor Genetics	RCV000666672	SCV004216359	likely pathogenic	Wilson disease	2023-08-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000666672	SCV004829545	uncertain significance	Wilson disease	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant, c.3452G>A, replaces arginine with histidine at codon 1151 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies showed that this variant has a 1.3 fold reduced affinity to ATP compared with wild-type (PMID: 15205462). This variant has been reported in many individuals affected with autosomal recessive Wilson disease (PMID: 10544227, 21219664, 27022412, 27398169, 27982432). In one affected individual, this variant was observed in the compound heterozygous state with a second pathogenic variant (PMID: 10544227), indicating that this variant contributes to disease. Additionally, in three affected individuals, a second co-occurring pathogenic ATP7B variant was detected, however, it is unknown whether these variants are in cis or trans (PMID: 27398169, 35222532, 36253962). This variant has been identified in 3/249588 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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.
Counsyl	RCV000666672	SCV000791002	likely pathogenic	Wilson disease	2017-10-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000666672	SCV001455587	uncertain significance	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing