NM_018451.5(CPAP):c.2462C>T (p.Thr821Met) AND Microcephaly 6, primary, autosomal recessive

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Apr 27, 2017
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:: RCV000023763.15

Allele description [Variation Report for NM_018451.5(CPAP):c.2462C>T (p.Thr821Met)]

NM_018451.5(CPAP):c.2462C>T (p.Thr821Met)

Gene:

CPAP:centrosome assembly and centriole elongation protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.13

Genomic location:

Preferred name:

NM_018451.5(CPAP):c.2462C>T (p.Thr821Met)

HGVS:

NC_000013.11:g.24905576G>A
NG_009165.2:g.22372C>T
NM_018451.5:c.2462C>TMANE SELECT
NP_060921.3:p.Thr821Met
NC_000013.10:g.25479714G>A
NM_018451.3:c.2462C>T
NM_018451.4:c.2462C>T
NR_047594.2:n.2629C>T
NR_047595.2:n.2629C>T

Protein change:

T821M; THR821MET

Links:

OMIM: 609279.0005; dbSNP: rs144938364

NCBI 1000 Genomes Browser:

rs144938364

Molecular consequence:

NM_018451.5:c.2462C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_047594.2:n.2629C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_047595.2:n.2629C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Microcephaly 6, primary, autosomal recessive
Identifiers:: MONDO: MONDO:0012029; MedGen: C1842109; Orphanet: 2512; OMIM: 608393

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cytochrome oxidase subunit I, partial (mitochondrion) [Vertigo alpestris]
cytochrome oxidase subunit I, partial (mitochondrion) [Vertigo alpestris]
gi|364807260|gb|AEW67714.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045054	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2010)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000192660	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Uncertain significance (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000267246	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 20978018, 25741868
SCV001268380	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
East Asian	germline	unknown	4	not provided	not provided	not provided	not provided	reference population

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

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

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000045054.3

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

Description

In 2 sibs, born of consanguineous Iranian parents, with primary microcephaly-6 (MCPH6; 608393), Darvish et al. (2010) identified a homozygous 2462C-T transition in exon 7 of the CENPJ gene, resulting in a thr821-to-met (T821M) substitution, which may disrupt the TCP10 domain and interfere with normal protein function. The mutation was not found in 160 German and 190 Iranian controls. The patients had some additional features, including small ears, hypertelorism, notched nasal tip, seizures, joint stiffness, and wheelchair requirement.

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

From Genetic Services Laboratory, University of Chicago, SCV000192660.1

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

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267246.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	4	not provided	not provided	reference population	PubMed (2)

#	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		4	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001268380.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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

Last Updated: Nov 3, 2024

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