NM_000052.7(ATP7A):c.4168T>C (p.Ser1390Pro) AND Menkes kinky-hair syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 21, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002472153.2

Allele description [Variation Report for NM_000052.7(ATP7A):c.4168T>C (p.Ser1390Pro)]

NM_000052.7(ATP7A):c.4168T>C (p.Ser1390Pro)

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.4168T>C (p.Ser1390Pro)

HGVS:

NC_000023.11:g.78045514T>C
NG_013224.2:g.139818T>C
NM_000052.7:c.4168T>CMANE SELECT
NM_001282224.2:c.3934T>C
NP_000043.4:p.Ser1390Pro
NP_001269153.1:p.Ser1312Pro
NC_000023.10:g.77301011T>C
NM_000052.6:c.4168T>C
NR_104109.2:n.1341T>C

Protein change:

S1312P

Molecular consequence:

NM_000052.7:c.4168T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282224.2:c.3934T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_104109.2:n.1341T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV002768605	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9166584, 9385451, 17483305, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002768605

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Citations

PubMed

A serine-to-proline mutation in the copper-transporting P-type ATPase gene of the macular mouse.

Mori M, Nishimura M.

Mamm Genome. 1997 Jun;8(6):407-10.

PubMed [citation]

PMID:: 9166584

Occurrence of two missense mutations in Cu-ATPase of the macular mouse, a Menkes disease model.

Ohta Y, Shiraishi N, Nishikimi M.

Biochem Mol Biol Int. 1997 Nov;43(4):913-8.

PubMed [citation]

PMID:: 9385451

See all PubMed Citations (4)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768605.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Menkes disease (MIM#309400) and occipital horn syndrome (MIM#304150). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to proline. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transmembrane 8 domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The orthologous variant has been identified in the macular mouse, a murine model of human Menkes disease (PMID: 9166584, 9385451). Functional studies of the macular mutation failed to abolish copper transport to tyrosinase, however the intracellular distribution was affected (PMID: 17483305). Biochemical studies measuring copper levels in this patient determined that the copper level was reduced. (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Aug 4, 2024

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