Submissions for variant NM_000053.4(ATP7B):c.4213G>A (p.Gly1405Ser)

gnomAD frequency: 0.00025  dbSNP: rs189601972

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513406	SCV000608685	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ATP7B: PM3:Strong, PM2, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488645	SCV000694465	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.4213G>A (p.Gly1405Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 247972 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4213G>A has been reported in the literature in at-least one individual from a Wilson Disease patient cohort with at least 1 variant in ATP7B (example: Nayagam_2023). This report does not provide unequivocal conclusions about association of the variant with Wilson Disease. 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: 24253677, 36096368). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000670982	SCV000795914	uncertain significance	Wilson disease	2017-11-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513406	SCV000885051	uncertain significance	not provided	2018-04-04	criteria provided, single submitter	clinical testing	The ATP7B c.4213G>A; p.Gly1405Ser variant (rs189601972), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 444316). This variant is found in the general population with an overall allele frequency of 0.004% (11/275580 alleles) in the Genome Aggregation Database. The glycine at codon 1405 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Gly1405Ser variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670982	SCV000939130	uncertain significance	Wilson disease	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1405 of the ATP7B protein (p.Gly1405Ser). This variant is present in population databases (rs189601972, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 444316). 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. 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.
Baylor Genetics	RCV000670982	SCV001522520	uncertain significance	Wilson disease	2020-02-12	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000513406	SCV001713625	uncertain significance	not provided	2019-12-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000670982	SCV001977528	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000670982	SCV004844527	uncertain significance	Wilson disease	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1405 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Wilson disease in the literature. This variant has been identified in 11/279374 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000513406	SCV004848583	uncertain significance	not provided	2024-03-25	criteria provided, single submitter	clinical testing	The p.Gly1405Ser variant in ATP7B has not been reported in individuals with ATP7B-associated disorder(s). This variant has been identified in 0.18% (28/15284) of Latino/Admixed American chromosomes, including 1 homozygotes, by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 444316). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting.
Natera, Inc.	RCV000670982	SCV001454146	uncertain significance	Wilson disease	2020-04-15	no assertion criteria provided	clinical testing