NM_000052.7(ATP7A):c.1933C>T (p.Arg645Ter) AND Menkes kinky-hair syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 3, 2020
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:: RCV000193235.8

Allele description [Variation Report for NM_000052.7(ATP7A):c.1933C>T (p.Arg645Ter)]

NM_000052.7(ATP7A):c.1933C>T (p.Arg645Ter)

Gene:

ATP7A:ATPase copper transporting alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq21.1

Genomic location:

Preferred name:

NM_000052.7(ATP7A):c.1933C>T (p.Arg645Ter)

HGVS:

NC_000023.11:g.78011239C>T
NG_013224.2:g.105543C>T
NM_000052.7:c.1933C>TMANE SELECT
NM_001282224.2:c.1933C>T
NP_000043.4:p.Arg645Ter
NP_001269153.1:p.Arg645Ter
NP_001269153.1:p.Arg645Ter
NC_000023.10:g.77266736C>T
NM_000052.4:c.1933C>T
NM_000052.6:c.1933C>T
NM_001282224.1:c.1933C>T
p.Arg645*

Protein change:

R645*

Links:

dbSNP: rs72554640

NCBI 1000 Genomes Browser:

rs72554640

Molecular consequence:

NM_000052.7:c.1933C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282224.2:c.1933C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Menkes kinky-hair syndrome (MNK)
Synonyms:: Kinky hair disease; Copper transport disease; Menkes Disease
Identifiers:: MONDO: MONDO:0010651; MedGen: C0022716; Orphanet: 565; OMIM: 309400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000246657	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000844970	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	no assertion criteria provided	Pathogenic (Sep 18, 2018)	germline	clinical testing
SCV001338560	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 3, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7977350, 32005694, 11350187, 26117549, 8981948 Citation Link,
SCV004011996	Inherited Neuropathy Consortium Ii, University Of Miami	no assertion criteria provided	Uncertain significance (Jan 6, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]

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, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Indian Hindu	germline	yes	1	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

Diverse mutations in patients with Menkes disease often lead to exon skipping.

Das S, Levinson B, Whitney S, Vulpe C, Packman S, Gitschier J.

Am J Hum Genet. 1994 Nov;55(5):883-9.

PubMed [citation]

PMID:: 7977350
PMCID:: PMC1918324

See all PubMed Citations (7)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000246657.1

#	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000844970.1

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

Description

The observed variant c.1933C>T has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2 and LRT.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338560.1

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

Description

Variant summary: ATP7A c.1933C>T (p.Arg645X) 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 was absent in 183238 control chromosomes (gnomAD). c.1933C>T has been reported in the literature in multiple individuals affected with Menkes kinky-hair syndrome (e.g. Das_1994, Hahn_2001, Mohamed_2015, Tumer_1997). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite 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 Inherited Neuropathy Consortium Ii, University Of Miami, SCV004011996.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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

Last Updated: Mar 5, 2024

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