NM_001012614.2(CTBP1):c.991C>T (p.Arg331Trp) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 23, 2023
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:: RCV000211044.9

Allele description [Variation Report for NM_001012614.2(CTBP1):c.991C>T (p.Arg331Trp)]

NM_001012614.2(CTBP1):c.991C>T (p.Arg331Trp)

Genes:

CTBP1:C-terminal binding protein 1 [Gene - OMIM - HGNC]
CTBP1-AS:CTBP1 antisense RNA [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_001012614.2(CTBP1):c.991C>T (p.Arg331Trp)

HGVS:

NC_000004.12:g.1213028G>A
NG_052824.1:g.42302C>T
NM_001012614.2:c.991C>TMANE SELECT
NM_001328.3:c.1024C>T
NP_001012632.1:p.Arg331Trp
NP_001319.1:p.Arg342Trp
NC_000004.11:g.1206816G>A
NM_001012614.1:c.991C>T
NM_001328.2:c.1024C>T
NM_001377192.1:c.991C>T

Protein change:

R331W; ARG331TRP

Links:

OMIM: 602618.0001; dbSNP: rs869320802

NCBI 1000 Genomes Browser:

rs869320802

Molecular consequence:

NM_001012614.2:c.991C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001328.3:c.1024C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000267836	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 23, 2023)	germline	clinical testing	Citation Link,
SCV001447737	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001577979	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 18, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31041561, 29878067, 28955726, 27094857, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267836

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 23, 2023)

germline

clinical testing

Citation Link,

SCV001447737

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 23, 2020)

germline

clinical testing

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

SCV001577979

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 18, 2020)

germline

clinical testing

PubMed (5)
[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	1	not provided	clinical testing
not provided	germline	unknown	not provided	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

A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.

Beck DB, Subramanian T, Vijayalingam S, Ezekiel UR, Donkervoort S, Yang ML, Dubbs HA, Ortiz-Gonzalez XR, Lakhani S, Segal D, Au M, Graham JM Jr, Verma S, Waggoner D, Shinawi M, Bönnemann CG, Chung WK, Chinnadurai G.

Neurogenetics. 2019 Aug;20(3):129-143. doi: 10.1007/s10048-019-00578-1. Epub 2019 Apr 30.

PubMed [citation]

PMID:: 31041561
PMCID:: PMC8078134

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000267836.9

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27094857, 28135719, 28191890, 29878067, 31041561, 32167997, 31618753, 33192249, 28252636, 31785789, 36341169, 34732400)

#	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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447737.1

#	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	1	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001577979.3

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

Description

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CTBP1 protein function (PMID: 31041561). This variant has been observed in individual(s) with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (PMID: 31041561, 29878067, 28955726, 27094857). In at least one individual the variant was observed to be de novo. This variant is also known as c.991C>T (p.R331W) in the literature. ClinVar contains an entry for this variant (Variation ID: 225758). This sequence change replaces arginine with tryptophan at codon 342 of the CTBP1 protein (p.Arg342Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan.

#	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: May 12, 2024

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