rs1557045250
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4_StrongPP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA415086073/MONDO:0010305/027
Frequency
Consequence
NM_005629.4 missense
Scores
Clinical Significance
Conservation
Publications
- creatine transporter deficiencyInheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC6A8 | NM_005629.4 | c.1145C>T | p.Pro382Leu | missense_variant | Exon 8 of 13 | ENST00000253122.10 | NP_005620.1 | |
| SLC6A8 | NM_001142805.2 | c.1115C>T | p.Pro372Leu | missense_variant | Exon 8 of 13 | NP_001136277.1 | ||
| SLC6A8 | NM_001142806.1 | c.800C>T | p.Pro267Leu | missense_variant | Exon 8 of 13 | NP_001136278.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00 AC: 0AN: 114879 AF XY: 0.00
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1044291Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 336455
GnomAD4 genome
ClinVar
Submissions by phenotype
Creatine transporter deficiency Pathogenic:5Other:1
- -
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. -
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. -
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. -
- -
- -
not provided Pathogenic:1
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) -
Intellectual disability Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at