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

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000578214	SCV001432146	pathogenic	Intellectual disability, autosomal dominant 56	2020-02-24	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV001281635	SCV001468971	pathogenic	not provided		criteria provided, single submitter	clinical testing
GeneDx	RCV001281635	SCV002526557	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing	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)
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000578214	SCV002574942	pathogenic	Intellectual disability, autosomal dominant 56	2022-09-16	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000578214	SCV002580042	likely pathogenic	Intellectual disability, autosomal dominant 56	2022-06-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001281635	SCV003297510	pathogenic	not provided	2024-12-05	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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 also known as c.2669C>T (p.Pro890Leu). ClinVar contains an entry for this variant (Variation ID: 488418). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CLTC protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000578214	SCV005086158	pathogenic	Intellectual disability, autosomal dominant 56	2023-07-17	criteria provided, single submitter	clinical testing	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
OMIM	RCV000578214	SCV000680085	pathogenic	Intellectual disability, autosomal dominant 56	2021-10-20	no assertion criteria provided	literature only
Gene Discovery Core-Manton Center, Boston Children's Hospital	RCV000578214	SCV000930678	uncertain significance	Intellectual disability, autosomal dominant 56	2019-02-05	no assertion criteria provided	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000578214	SCV001442973	likely pathogenic	Intellectual disability, autosomal dominant 56	2020-09-14	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000578214	SCV001450717	pathogenic	Intellectual disability, autosomal dominant 56	2020-07-03	no assertion criteria provided	clinical testing