chr13-51946369-G-A

Variant names:

• chr13-51946369-G-A
• rs201038679
• NM_000053.4:c.2975C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.2975C>T​(p.Pro992Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P992H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.94
• Publications: 85 publications found

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000053.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 13-51946369-G-A is Pathogenic according to our data. Variant chr13-51946369-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.2975C>T	p.Pro992Leu	missense_variant	Exon 13 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.2975C>T	p.Pro992Leu	missense_variant	Exon 13 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248476 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461152 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726848

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5382

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000671 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:13

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 992 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 in yeast cells showed that this variant caused a disruption to copper uptake and transport, a severe deficit in a complementation assay, and temperature sensitivity (PMID: 9837819, 22240481). In addition, functional studies conducted in CHO cells showed that this variant caused a deficit in copper tolerance, higher levels of copper, and abnormal sub-cellular localization compared to wild type (PMID: 26032686). This variant has been reported in many individuals affected with Wilson disease (PMID: 9199563, 9671269, 9829905, 11690702, 16649058, 16696937, 18034201, 23235335, 23843956, 27022412, 27398169, 27638368) and was identified as a founder variant in a Chinese population (PMID: 23843956). In a number of these individuals, this variant was reported in the homozygous state or compound heterozygous state (PMID: 9199563, 16649058, 23843956, 27022412, 27638368), indicating that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 10/279878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Apr 02, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant. The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (> 0.75, sensitivity 0.96 and precision 0.92)]. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.2975C>T; p.Pro992Leu variant (rs201038679), is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with Wilson disease (Gu 2013, Nanji 1997, Seidel 2001, Wu 2006, Yu 2017). This variant is also reported in ClinVar (Variation ID: 188831). It is found in the East Asian population with an allele frequency of 0.046% (9/19520 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.905). Consistent with these predictions, in vitro functional analyses demonstrate impaired protein trafficking and decreased copper transport activity (Huster 2012, Zhu 2015). Based on available information, the p.Pro992Leu variant is considered to be pathogenic. References: Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. PMID: 23843956. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Nanji MS et al. Haplotype and mutation analysis in Japanese patients with Wilson disease. Am J Hum Genet. 1997 Jun;60(6):1423-9. PMID: 9199563. Seidel J et al. Disturbed copper transport in humans. Part 2: mutations of the ATP7B gene lead to Wilson disease (WD). Cell Mol Biol (Noisy-le-grand). 2001;47 Online Pub:OL149-57. PMID: 11936861. Wu ZY et al. Mutation analysis of 218 Chinese patients with Wilson disease revealed no correlation between the canine copper toxicosis gene MURR1 and Wilson disease. J Mol Med (Berl). 2006 May;84(5):438-42. PMID: 16649058. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34. PMID: 28212618. Zhu M et al. Defective roles of ATP7B missense mutations in cellular copper tolerance and copper excretion. Mol Cell Neurosci. 2015 Jul;67:31-6. PMID: 26032686.

Jun 28, 2025

Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino"

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2014

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Oct 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 992 of the ATP7B protein (p.Pro992Leu). This variant is present in population databases (rs201038679, gnomAD 0.05%). This missense change has been observed in individual(s) with Wilson disease (PMID: 23843956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188831). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 9837819). For these reasons, this variant has been classified as Pathogenic.

Nov 12, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP7B c.2975C>T (p.Pro992Leu) results in a non-conservative amino acid change in the predicted cation chanel TM6 domain of the encoded protein sequence. Another variant in the same codon c.2975C>A (p.P992H) has been reported to be associated with Wilson Disease (HGMD; Kumar et al., Clin Genet, 2005; Schushan et al. Metallomics, 2012). Five of five in-silico tools predict a damaging effect of the variant on protein function. This mutation is predicted to disrupt the function of the cation channel and/or the formation of the transmembrane domain. The variant allele was found at a frequency of 3.6e-05 in 276312 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (3.6e-05 vs 0.0054), allowing no conclusion about variant significance. c.2975C>T has been reported in the literature in multiple individuals affected with Wilson Disease (Dong_2016) with homozygous or compound heterozygous genotypes. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Apr 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly impaired copper uptake and transport (PMID: 9837819, 22240481, 26032686); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26032686, 30366773, 28855492, 28212618, 30384382, 27398169, 11936861, 30655162, 30275481, 32005694, 32289814, 33763395, 34539730, 34240825, 34324271, 33668890, 32113134, 35314707, 35257483, 24253677, 22240481, 22692182, 9199563, 23843956, 35470480, 9837819)

Dec 29, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2

Inborn genetic diseases Pathogenic:1

Sep 19, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P992L pathogenic mutation (also known as c.2975C>T), located in coding exon 13 of the ATP7B gene, results from a C to T substitution at nucleotide position 2975. The proline at codon 992 is replaced by leucine, an amino acid with similar properties. This mutation has been identified in multiple individuals with Wilson disease in the compound heterozygous or homozygous state (Nanji MS et al. Am. J. Hum. Genet., 1997 Jun;60:1423-9; Loudianos G et al. Hum. Mutat., 1998;12:89-94; Wu ZY et al. J. Mol. Med., 2006 May;84:438-42; Mak CM et al. J. Hum. Genet., 2008 Nov;53:55-63; Li K et al. J. Hum. Genet., 2013 Feb;58:67-72; Gu S et al. PLoS ONE, 2013 Jul;8:e66526). In addition, expression of this mutation in Sf9 cells showed partial copper uptake with normal phosphorylation activity (Huster D et al. Gastroenterology, 2012 Apr;142:947-956.e5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.;.;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.9	D;D;D;D;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Vest4		0.99
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201038679; hg19: chr13-52520505; COSMIC: COSV105842084;