rs201038679

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.94

Variant links:

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 links:

ATP7B (HGNC:):

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a transmembrane_region Helical (size 21) in uniprot entity ATP7B_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

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 [Likely_pathogenic]. Clinvar id is 188831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51946369-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2975C>T	p.Pro992Leu	missense_variant	13/21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2975C>T	p.Pro992Leu	missense_variant	13/21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248476

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

134948

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461152

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000437

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM3_VeryStrong+PP4+PS3 -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 27, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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). 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 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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2018	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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2022	PP3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2024	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) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2017

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

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;.;.;.;.;.

PrimateAI

Pathogenic

0.90

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

Polyphen

1.0

D;D;D;B;B;D

Vest4

0.99

MutPred

0.96

Loss of glycosylation at P992 (P = 0.0325);.;.;.;.;.;

MVP

0.97

MPC

0.38

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over