NM_000053.4(ATP7B):c.2975C>T (p.Pro992Leu) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000169179.32

Allele description [Variation Report for NM_000053.4(ATP7B):c.2975C>T (p.Pro992Leu)]

NM_000053.4(ATP7B):c.2975C>T (p.Pro992Leu)

Gene:

ATP7B:ATPase copper transporting beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.3

Genomic location:

Preferred name:

NM_000053.4(ATP7B):c.2975C>T (p.Pro992Leu)

HGVS:

NC_000013.11:g.51946369G>A
NG_008806.1:g.70126C>T
NM_000053.4:c.2975C>TMANE SELECT
NM_001005918.3:c.2354C>T
NM_001243182.2:c.2642C>T
NM_001330578.2:c.2741C>T
NM_001330579.2:c.2723C>T
NP_000044.2:p.Pro992Leu
NP_001005918.1:p.Pro785Leu
NP_001230111.1:p.Pro881Leu
NP_001317507.1:p.Pro914Leu
NP_001317508.1:p.Pro908Leu
NC_000013.10:g.52520505G>A
NM_000053.2:c.2975C>T
NM_000053.3:c.2975C>T
P35670:p.Pro992Leu

Protein change:

P785L

Links:

UniProtKB: P35670#VAR_000749; dbSNP: rs201038679

NCBI 1000 Genomes Browser:

rs201038679

Molecular consequence:

NM_000053.4:c.2975C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2354C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.2642C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.2741C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2723C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Wilson disease (WND)
Synonyms:: Wilson's disease; Hepatolenticular degeneration
Identifiers:: MONDO: MONDO:0010200; MedGen: C0019202; Orphanet: 905; OMIM: 277900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220416	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Jun 14, 2014)	unknown	literature only	PubMed (12) [See all records that cite these PMIDs] 9671269, 23843956, 22240481, 11690702, 9837819, 16649058, 18034201, 17717039, 9829905, 16696937, 23235335, 9199563 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000894015	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 23, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000916639	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 12, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000944460	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23843956, 9837819, 28492532
SCV001158016	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Jun 27, 2023)	germline	clinical testing	Citation Link,
SCV001459711	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001739503	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 28, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001977289	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004216269	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004845446	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 9199563, 9671269, 9829905, 9837819, 11690702, 16649058, 16696937, 18034201, 22240481, 23235335, 23843956, 26032686, 27022412, 27398169, 27638368, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing
East asia	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes.

de Bie P, Muller P, Wijmenga C, Klomp LW.

J Med Genet. 2007 Nov;44(11):673-88. Epub 2007 Aug 23. Review.

PubMed [citation]

PMID:: 17717039
PMCID:: PMC2752173

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (18)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Counsyl, SCV000220416.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (12)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000894015.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916639.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000944460.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158016.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001459711.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital, SCV001739503.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East asia	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001977289.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004216269.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004845446.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (16)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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