VCV000005301.35 - ClinVar

NM_004715.5(CTDP1):c.863+389C>T

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004715.5(CTDP1):c.863+389C>T

Variation ID: 5301 Accession: VCV000005301.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q23 18: 79710825 (GRCh38) [ NCBI UCSC ] 18: 77470825 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004715.5:c.863+389C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001202504.1:c.506+389C>T		intron variant
NM_001318511.2:c.863+389C>T		intron variant
NM_048368.4:c.863+389C>T		intron variant
NC_000018.10:g.79710825C>T
NC_000018.9:g.77470825C>T
NG_007988.1:g.36025C>T
LRG_236:g.36025C>T
LRG_236t1:c.863+389C>T

... more HGVS ... less HGVS

Protein change

Other names

IVS6, C-T, +389

Canonical SPDI

NC_000018.10:79710824:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA340394 Genetic Testing Registry (GTR): GTR000570472 OMIM: 604927.0001 dbSNP: rs113994102 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CTDP1		-	-	GRCh38 GRCh38 GRCh37	551	736

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital cataracts-facial dysmorphism-neuropathy syndrome	Pathogenic (2)	no assertion criteria provided	Oct 1, 2004	RCV000005622.4
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV001092097.27
Charcot-Marie-Tooth disease	Pathogenic (1)	no assertion criteria provided	-	RCV000789083.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002125607.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 14517542‚ 23408394‚ 24690360‚ 29174527 Comment: For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in multiple RNA … (more) For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 14517542). ClinVar contains an entry for this variant (Variation ID: 5301). This variant has been observed in individual(s) with congenital cataracts, facial dysmorphism, and neuropathy (PMID: 14517542, 23408394, 24690360, 29174527). It is commonly reported in individuals of Romani ancestry (PMID: 24690360, 29174527). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the CTDP1 gene. It does not directly change the encoded amino acid sequence of the CTDP1 protein. (less)
Pathogenic (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248460.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: CTDP1: PM3:Very Strong, PM2, PS3:Supporting Number of individuals with the variant: 13
Pathogenic (Oct 01, 2004)	no assertion criteria provided Method: literature only	CONGENITAL CATARACTS, FACIAL DYSMORPHISM, AND NEUROPATHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025804.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 14517542‚ 15322984 Comment on evidence: In Rudari Vlax Roma (Gypsies) with congenital cataracts with facial dysmorphism and neuropathy (CCFDN; 604168), Varon et al. (2003) found perfect segregation of the disease … (more) In Rudari Vlax Roma (Gypsies) with congenital cataracts with facial dysmorphism and neuropathy (CCFDN; 604168), Varon et al. (2003) found perfect segregation of the disease phenotype with a C-to-T transition in an antisense Alu element in intron 6 of the CTDP1 gene (IVS6+389C-T). Screening of 887 unaffected population controls found a 6.9% carrier rate among the Rudari, in close agreement with predictions based on CCFDN prevalence; an average carrier rate of 0.6% in other Gypsy populations; and a rate of 0.0% among non-Gypsy Europeans. RT-PCR and sequencing analysis identified a rare mechanism of aberrant splicing in which the donor site created by the C-T transition activates an upstream cryptic acceptor site, resulting in the insertion of 95 nucleotides of the Alu sequence in the processed CTDP1 mRNA. This mechanism had been identified previously only in ornithine aminotransferase deficiency (258870.0023). The insertion in the CTDP1 mRNA results in a premature termination signal 17 codons downstream of exon 6, with the mutant transcript expected to undergo nonsense-mediated decay or lead to a nonfunctional protein lacking the nuclear localization signal. Varon et al. (2003) observed an abnormal product in all cell types studied, regardless of their involvement in the clinical phenotype. Morar et al. (2004) used the IVS6+389C-T mutation and 4 other private mutations among the Roma (Gypsies) to infer some of the missing parameters relevant to the comprehensive characterization of the population history of the Gypsies. Sharing of mutations and high carrier rates supported a strong founder effect. (less)
Pathogenic (-)	no assertion criteria provided Method: literature only	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000928432.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Publications: PubMed (1) PubMed: 16194727
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979101.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979376.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
not provided (-)	no classification provided Method: literature only	Congenital cataracts-facial dysmorphism-neuropathy syndrome Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000041120.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301787 BookShelf: NBK25565 BookShelf: NBK25565

Comment:

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 14517542). ClinVar contains an entry for this variant (Variation ID: 5301). This variant has been observed in individual(s) with congenital cataracts, facial dysmorphism, and neuropathy (PMID: 14517542, 23408394, 24690360, 29174527). It is commonly reported in individuals of Romani ancestry (PMID: 24690360, 29174527). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the CTDP1 gene. It does not directly change the encoded amino acid sequence of the CTDP1 protein.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CTDP1-Related Congenital Cataracts, Facial Dysmorphism, and Neuropathy.	Adam MP	-	2022	PMID: 20301787
Genotypic and phenotypic spectrum of the most common causative genes of Charcot-Marie-Tooth disease in Hungarian patients.	Milley GM	Neuromuscular disorders : NMD	2018	PMID: 29174527
Congenital cataract, facial dysmorphism and demyelinating neuropathy (CCFDN) in 10 Czech Gypsy children--frequent and underestimated cause of disability among Czech Gypsies.	Lassuthova P	Orphanet journal of rare diseases	2014	PMID: 24690360
A case of congenital cataracts, facial dysmorphisms, neuropathy, and hyperkinetic movement disorder.	Manganelli F	Movement disorders : official journal of the Movement Disorder Society	2013	PMID: 23408394
Congenital cataract facial dysmorphism neuropathy syndrome: a clinically recognizable entity.	Shabo G	Pediatric neurology	2005	PMID: 16194727
Mutation history of the roma/gypsies.	Morar B	American journal of human genetics	2004	PMID: 15322984
Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome.	Varon R	Nature genetics	2003	PMID: 14517542

Text-mined citations for rs113994102 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_004715.5(CTDP1):c.863+389C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113994102 ...