13-51974407-G-T

Variant names:

• chr13-51974407-G-T
• rs572147914
• NM_000053.4:c.813C>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000053.4(ATP7B):​c.813C>A​(p.Cys271*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: ATP7B NM_000053.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 0.801

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-51974407-G-T is Pathogenic according to our data. Variant chr13-51974407-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51974407-G-T is described in Lovd as [Pathogenic]. Variant chr13-51974407-G-T is described in Lovd as [Likely_pathogenic]. Variant chr13-51974407-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.813C>A	p.Cys271*	stop_gained	Exon 2 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.813C>A	p.Cys271*	stop_gained	Exon 2 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000968 AC: 24 AN: 247982 Hom.: 0 AF XY: 0.000149 AC XY: 20 AN XY: 134616

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461712 Hom.: 0 Cov.: 34 AF XY: 0.0000605 AC XY: 44 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000745 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:15

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 2 of the ATP7B gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous and homozygous states in many individuals affected with Wilson disease and is one of the most common mutations in India associated with Wilson disease (PMID: 9887381, 16133174, 17264425, 21034864, 21645214, 23518715, 23551039, 24094725, 30426382, 31059521). This variant has been identified in 24/247982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gained variant c.813C>A(p.Cys271Ter) in the ATP7B gene has been reported previously in multiple individuals affected with Wilson disease. It is the most prevalent mutation with an allele frequency of 16%, 10%, and 20.2% in eastern, southern, and western Indian populations respectively (Singh N, et al., 2019; Aggarwal A, et al., 2013). This variant is reported with the allele frequency 0.01% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic by multiple submitters. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

May 31, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 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.813C>A (p.Cys271X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.4e-05 in 244686 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (9.4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.813C>A, has been reported in the literature in multiple individuals affected with Wilson Disease (Mukherjee_2014, Coffey_2013, Duc_1998). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys271*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs572147914, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 21034864, 30426382, 31059521). ClinVar contains an entry for this variant (Variation ID: 188930). For these reasons, this variant has been classified as Pathogenic. -

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2013

Arcensus

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys271X variant in ATP7B has been previously reported in many homozygous and compound heterozygous individuals with Wilson disease, and segregated with disease in at least two affected relatives (Aggarwal 2013, Coffey 2013, Duc 1998, Gupta 2005, Khan 2018, Lee 2011, Mukerjee 2014, Santhosh 2006). The majority of these individuals were from the Indian subcontinent. This variant has also been identified in 0.07% (23/30584) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 271, which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Moderate, PP4. -

not provided Pathogenic:6

Dec 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Most common pathogenic variant identified in individuals with Wilson disease in India (PMID: 31059521, 24094725); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 25525159, 30426382, 34643937, 35342245, 9887381, 24094725, 23551039, 23518715, 31059521) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM2_moderate, PVS1 -

Oct 26, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Intellectual disability, Wolff type Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained p.C271Ter in ATP7B (NM_000053.3) has been previously reported in multiple patients affected with Wilson disease (Aggarwal A et al, 2013; Mukherjee S et al, 2014). It has been reported in the ClinVar database as Pathogenic. The p.C271Ter variant is observed in 2/978 (0.2045%) alleles from individuals of South Asian background in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -

ATP7B-related disorder Pathogenic:1

Mar 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATP7B c.813C>A variant is predicted to result in premature protein termination (p.Cys271*). This variant has been detected in the homozygous and compound heterozygous state in a large number of individuals with Wilson disease, particularly of East Indian descent (Duc et al. 1998. PubMed ID: 9887381; Mukherjee et al. 2014. PubMed ID: 24094725). It is listed as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/188930/). This variant is reported in 0.075% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ATP7B are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	0.98
Eigen	Benign	0.021
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.82	D
Vest4		0.91
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs572147914; hg19: chr13-52548543;