VCV000488418.15 - ClinVar

NM_004859.4(CLTC):c.2669C>T (p.Pro890Leu)

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.

(11)

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/Likely 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_004859.4(CLTC):c.2669C>T (p.Pro890Leu)

Variation ID: 488418 Accession: VCV000488418.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q23.1 17: 59677061 (GRCh38) [ NCBI UCSC ] 17: 57754422 (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	Feb 5, 2018	Jul 23, 2024	Jul 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004859.4:c.2669C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004850.1:p.Pro890Leu	missense
NM_001288653.2:c.2681C>T	NP_001275582.1:p.Pro894Leu	missense
NC_000017.11:g.59677061C>T
NC_000017.10:g.57754422C>T
NG_047043.1:g.62373C>T

... more HGVS ... less HGVS

Protein change

P890L, P894L

Other names

Canonical SPDI

NC_000017.11:59677060: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: CA400415888 OMIM: 118955.0004 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.
CLTC		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	768	908

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.
Intellectual disability, autosomal dominant 56	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV000578214.12
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 6, 2022	RCV001281635.7

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 (Feb 24, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 56 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001432146.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Number of individuals with the variant: 1 Clinical Features: Short stature (present) , Prominent digit pad (present) , Pes planus (present) , Pectus excavatum (present) , Muscular hypotonia (present) , Low anterior hairline (present) … (more) Short stature (present) , Prominent digit pad (present) , Pes planus (present) , Pectus excavatum (present) , Muscular hypotonia (present) , Low anterior hairline (present) , Long eyelashes (present) , Induced vaginal delivery (present) , Hyperlordosis (present) , Hyperextensibility of the knee (present) , Horizontal eyebrow (present) , High palate (present) , Global developmental delay (present) , Easy fatigability (present) , Dysharmonic delayed bone age (present) , Coombs-positive hemolytic anemia (present) , Abnormality of the nose (present) , Abnormal delivery (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Causasians Tissue: blood
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001468971.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021
Pathogenic (Sep 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 56 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Additional submitter: CUBI - Core Unit Bioinformatics, Berlin Institute of Health Accession: SCV002574942.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022	Clinical Features: Global developmental delay (present) , Hypotonia (present) , Short attention span (present) , Thick vermilion border (present) Sex: male Tissue: Blood
Likely pathogenic (Jun 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 56 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580042.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS2, PM1, PM2_SUP, PP2	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jun 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002526557.2 First in ClinVar: Jun 24, 2022 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as … (more) Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as P890L; This variant is associated with the following publications: (PMID: 28191890, 31036916, 31231135, 30979967, 26822784, 28135719, 30337205, 31776469, 31785789, 33004838, 29100083) (less)
Pathogenic (Sep 06, 2022)	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: SCV003297510.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 29100083 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 488418). This variant is also known as c.2669C>T (p.Pro890Leu). This missense change has been observed in individual(s) with CLTC-related conditions (PMID: 29100083). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 894 of the CLTC protein (p.Pro894Leu). (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 56 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086158.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 29100083‚ 30337205‚ 31036916‚ 31776469 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder 56 (MIM# 617854). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID:31776469). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity and has been reported as de novo in multiple unrelated individuals with intellectual disability and related symptoms (PMID:29100083, PMID:30337205, PMID:31036916 and PMID:31776469). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Uncertain significance (Feb 05, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability, autosomal dominant 56 Affected status: yes Allele origin: germline	Gene Discovery Core-Manton Center, Boston Children's Hospital Accession: SCV000930678.1 First in ClinVar: Aug 13, 2019 Last updated: Aug 13, 2019
Likely pathogenic (Sep 14, 2020)	no assertion criteria provided Method: clinical testing	Intellectual disability, autosomal dominant 56 Affected status: yes Allele origin: de novo	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV001442973.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Sex: male
Pathogenic (Jul 03, 2020)	no assertion criteria provided Method: clinical testing	Intellectual disability, autosomal dominant 56 Affected status: yes Allele origin: de novo	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001450717.1 First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020
Pathogenic (Oct 20, 2021)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 56 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000680085.2 First in ClinVar: Feb 05, 2018 Last updated: Oct 25, 2021	Publications: PubMed (1) PubMed: 29100083 Comment on evidence: In 3 unrelated patients (patients indvAA, CAUSES1, and 18052017) with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), Hamdan et al. (2017) identified a de novo … (more) In 3 unrelated patients (patients indvAA, CAUSES1, and 18052017) with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), Hamdan et al. (2017) identified a de novo heterozygous c.2669C-T transition (c.2669C-T, NM_004859.3) in the CLTC gene, predicted to result in a pro890-to-leu (P890L) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed. (less)
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Comment:

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as P890L; This variant is associated with the following publications: (PMID: 28191890, 31036916, 31231135, 30979967, 26822784, 28135719, 30337205, 31776469, 31785789, 33004838, 29100083)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 488418). This variant is also known as c.2669C>T (p.Pro890Leu). This missense change has been observed in individual(s) with CLTC-related conditions (PMID: 29100083). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 894 of the CLTC protein (p.Pro894Leu).

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder 56 (MIM# 617854). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID:31776469). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity and has been reported as de novo in multiple unrelated individuals with intellectual disability and related symptoms (PMID:29100083, PMID:30337205, PMID:31036916 and PMID:31776469). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy.	Nabais Sá MJ	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31776469
Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants.	Lecoquierre F	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036916
Neurotransmitter trafficking defect in a patient with clathrin (CLTC) variation presenting with intellectual disability and early-onset parkinsonism.	Manti F	Parkinsonism & related disorders	2019	PMID: 30337205
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.	Hamdan FF	American journal of human genetics	2017	PMID: 29100083

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004859.4(CLTC):c.2669C>T (p.Pro890Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...