NM_000053.4(ATP7B):c.2906G>A (p.Arg969Gln) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 1, 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:: RCV000270891.15

Allele description [Variation Report for NM_000053.4(ATP7B):c.2906G>A (p.Arg969Gln)]

NM_000053.4(ATP7B):c.2906G>A (p.Arg969Gln)

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.2906G>A (p.Arg969Gln)

HGVS:

NC_000013.11:g.51946438C>T
NG_008806.1:g.70057G>A
NM_000053.4:c.2906G>AMANE SELECT
NM_001005918.3:c.2285G>A
NM_001243182.2:c.2573G>A
NM_001330578.2:c.2672G>A
NM_001330579.2:c.2654G>A
NP_000044.2:p.Arg969Gln
NP_001005918.1:p.Arg762Gln
NP_001230111.1:p.Arg858Gln
NP_001317507.1:p.Arg891Gln
NP_001317508.1:p.Arg885Gln
NC_000013.10:g.52520574C>T
NM_000053.3:c.2906G>A
P35670:p.Arg969Gln

Protein change:

R762Q; ARG969GLN

Links:

UniProtKB: P35670#VAR_000747; OMIM: 606882.0018; dbSNP: rs121907996

NCBI 1000 Genomes Browser:

rs121907996

Molecular consequence:

NM_000053.4:c.2906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2285G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.2573G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.2672G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.2654G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329795	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Sep 27, 2016)	germline	clinical testing	Citation Link,
SCV001716159	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:22692182,
SCV005042393	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329795

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Sep 27, 2016)

germline

clinical testing

Citation Link,

SCV001716159

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 14, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

PMID:22692182,

SCV005042393

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Apr 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000329795.5

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

Description

The R969Q pathogenic variant in the ATP7B gene has been reported previously, using alternate nomenclature A970Q, in association with Wilson disease when present in the homozygous state or when in trans with another disease-causing variant (Figus et al., 1995). The R969Q variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R969Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show R969Q had a significant decrease in copper uptake compared to wild type (Huster et al., 2012). Missense variants in the same and nearby residues (R969W, A971V, T974M) have been reported in the Human Gene Mutation Database in association with Wilson disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R969Q as a pathogenic variant.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV001716159.2

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

Description

PS3, PS4_moderate, PM2, PP3, PP4

#	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		2	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV005042393.6

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

Description

ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting

#	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

Last Updated: Oct 20, 2024

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