NM_000053.4(ATP7B):c.4039G>A (p.Gly1347Ser) AND Wilson disease

Germline classification:: Conflicting interpretations of pathogenicity (9 submissions)
Last evaluated:: Jul 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000145281.31

Allele description [Variation Report for NM_000053.4(ATP7B):c.4039G>A (p.Gly1347Ser)]

NM_000053.4(ATP7B):c.4039G>A (p.Gly1347Ser)

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.4039G>A (p.Gly1347Ser)

HGVS:

NC_000013.11:g.51935678C>T
NG_008806.1:g.80817G>A
NM_000053.4:c.4039G>AMANE SELECT
NM_001005918.3:c.3418G>A
NM_001243182.2:c.3706G>A
NM_001330578.2:c.3805G>A
NM_001330579.2:c.3787G>A
NP_000044.2:p.Gly1347Ser
NP_001005918.1:p.Gly1140Ser
NP_001230111.1:p.Gly1236Ser
NP_001317507.1:p.Gly1269Ser
NP_001317508.1:p.Gly1263Ser
NC_000013.10:g.52509814C>T
NM_000053.3:c.4039G>A
P35670:p.Gly1347Ser

Protein change:

G1140S

Links:

UniProtKB: P35670#VAR_076973; dbSNP: rs587783318

NCBI 1000 Genomes Browser:

rs587783318

Molecular consequence:

NM_000053.4:c.4039G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.3418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.3706G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.3805G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.3787G>A - 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
SCV000192358	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Likely pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001221182	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24555712, 28492532
SCV001437434	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 31, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24555712, 34426522, 36112267 Citation Link,
SCV001455573	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV001977531	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003835963	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 22, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004176655	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004563490	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely pathogenic (Oct 13, 2023)	germline	clinical testing	Citation Link,
SCV004844556	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24555712, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	8	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee.

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

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 (6)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000192358.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001221182.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1347 of the ATP7B protein (p.Gly1347Ser). This variant is present in population databases (rs587783318, gnomAD 0.08%). This missense change has been observed in individual(s) with Wilson disease (PMID: 24555712). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 157956). 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%. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001437434.3

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

Description

Variant summary: ATP7B c.4039G>A (p.Gly1347Ser) 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 0.00012 in 243552 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00012 vs 0.0054), allowing no conclusion about variant significance. c.4039G>A has been reported in the literature in compound heterozygous individuals affected with Wilson Disease (Forbes_2014, Nagral_2023) with evidence of familial segregation. These data indicate that the variant is likely associated with 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: 24555712, 34426522, 36112267). ClinVar contains an entry for this variant (Variation ID: 157956). Based on the evidence outlined above, the variant was classified as likely 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 Natera, Inc., SCV001455573.1

#	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 Genome-Nilou Lab, SCV001977531.1

#	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, SCV003835963.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004176655.1

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

Description

The missense c.4039G>A (p.Gly1347Ser) variant in ATP7B gene has been reported in compound heterozygote state in individuals in at least two family members affected with Wilson Disease (Forbes N et al. 2014). It has also been observed to segregate with disease in related individuals. The p.Gly1347Ser variant has allele frequency 0.01% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. The amino acid change p.Gly1347Ser in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1347 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Likely Pathogenic.

#	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		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563490.1

#	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.4039G>A; p.Gly1347Ser variant (rs587783318) is reported in the literature in the compound heterozygous state in individuals and segregates with disease in at least one family affected with Wilson disease (Forbes 2014, Nagral 2023). This variant is also reported in ClinVar (Variation ID: 157956), and is found in the general population with an overall allele frequency of 0.011% (31/274940 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.942). Based on available information, this variant is considered to be likely pathogenic. References: Forbes N et al. Evidence for synergistic effects of PRNP and ATP7B mutations in severe neuropsychiatric deterioration. BMC Med Genet. 2014 Feb 20;15:22. PMID: 24555712. Nagral A et al. Genomic Variations in ATP7B Gene in Indian Patients with Wilson Disease. Indian J Pediatr. 2023 Mar;90(3):240-248. PMID: 36112267.

#	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 All of Us Research Program, National Institutes of Health, SCV004844556.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (2)

Description

This variant introduces an AG dinucleotide 18 bases downstream of a splice site and replaces glycine with serine at codon 1347 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 been observed in the compound heterozygous state in two siblings affected with autosomal recessive Wilson disease (PMID: 24555712), indicating that this variant contributes to disease. This variant has been identified in 31/274940 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		8	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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