Submissions for variant NM_005629.4(SLC6A8):c.1145C>T (p.Pro382Leu)

dbSNP: rs1557045250

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000640931	SCV003852669	likely pathogenic	Creatine transporter deficiency	2022-12-08	reviewed by expert panel	curation	The NM_005629.4:c.1145C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 382 (p.Pro382Leu). This variant is absent from gnomADv2.1.1, and has been reported in two individuals in the literature. In one affected individual in the literature, the ratio of urine Creatine to Creatinine was >99th percentile of normal, and reduced creatine uptake in patient fibroblasts was reported. In silico predictor REVEL suggests this variant will have a damaging / pathogenic effect on the protein (score=0.906). There is a ClinVar entry for this variant (Variation ID: 533700, 1 star review status) with 5 submitters classifying the variant with conflicting interpretations (Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine transporter deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PP4_Strong, PM2_Supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640931	SCV000762535	pathogenic	Creatine transporter deficiency	2023-10-30	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 382 of the SLC6A8 protein (p.Pro382Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of creatine transporter deficiency (PMID: 19188083, 30885608; Invitae). ClinVar contains an entry for this variant (Variation ID: 533700). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC6A8 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC6A8 function (PMID: 22281021, 30885608, 32207963). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000640931	SCV001428483	pathogenic	Creatine transporter deficiency	2019-02-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001255373	SCV001431703	pathogenic	Intellectual disability	2020-08-03	criteria provided, single submitter	clinical testing	The variant c.1145C>T, p.(Pro382Leu) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was M.The variant likely explains the NDD in this individual.
National Institute of Neuroscience, National Center of Neurology and Psychiatry	RCV000640931	SCV001438321	pathogenic	Creatine transporter deficiency		criteria provided, single submitter	research
GeneDx	RCV002251491	SCV002522014	pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	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: 22281021, 23408511, 33192443, 30885608, 33624935, 19188083, 33911214, 32207963, 37587458, 37662495, 37850681, 34050321)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000640931	SCV002764894	likely pathogenic	Creatine transporter deficiency	2021-10-06	criteria provided, single submitter	clinical testing
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	RCV000640931	SCV001156348	not provided	Creatine transporter deficiency		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-03-2018 by GTR ID 500031. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.