rs397515558
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PM2_SupportingPS4_SupportingPP4_StrongPM6
This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1631C>T in SLC6A8 is a missense variant predicted to cause substitution of Proline with Leucine (p.Pro544Leu) at amino acid 544 in the 12th of 13 exons. This variant is absent from gnomAD v2.1.1, (PM2_Supporting). The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). This variant was reported in a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. Urine analysis showed an increased creatine/creatinine ratio (1.83; n.v. 0.03–0.92) with normal guanidinoacetate/creatinine ratio (0.024; n.v. 0.023–0.214) (1 point). Brain MRI with angiography and perfusion study was normal, while 1H-MRS revealed a consistent decrease in the creatine peak (Fig. 2) (3 points). Full sequencing of the SLC6A8 gene was reported. (PMID:17553121) (PP4_Strong). This variant was reported in a proband with an increased urine creatine/creatinine ratio of 2.0 (normal range 0.017–0.72), the proband’s brother also was affected and had elevated urine ratios and was hemizygous for the variant, while their mother was heterozygous for the same variant (PMID:15690373). (PS4_Supporting). A female proband presented with learning disabilities, seizures and significantly reduced creatine by 1 H-MRS (fig. 1). The patient had normal urine creatine/creatinine ratio (0.38 mmol/mmol). Molecular genetic testing identified the heterozygous variant SLC6A8 (c.1631C>T, p.(Pro544Leu)). Segregation analysis including both parents revealed that the variant was de novo in the patient (PMID:37708665) (PM6). This variant was assessed for co-segregation evidence (PP1) and functional evidence (PS3), but in both cases did not meet the specifications (PP1_Not Met, PS3_Not Met). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant 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 1.1.0). PM2_Supporting, PP3, PP4_Strong, PS4_Supporting, PM6.(Classification approved by the ClinGen CCDS VCEP on Oct. 26, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA345034/MONDO:0010305/027
Frequency
Consequence
NM_005629.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC6A8 | NM_005629.4 | c.1631C>T | p.Pro544Leu | missense_variant | 12/13 | ENST00000253122.10 | NP_005620.1 | |
| SLC6A8 | NM_001142805.2 | c.1601C>T | p.Pro534Leu | missense_variant | 12/13 | NP_001136277.1 | ||
| SLC6A8 | NM_001142806.1 | c.1286C>T | p.Pro429Leu | missense_variant | 12/13 | NP_001136278.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC6A8 | ENST00000253122.10 | c.1631C>T | p.Pro544Leu | missense_variant | 12/13 | 1 | NM_005629.4 | ENSP00000253122.5 | ||
| SLC6A8 | ENST00000430077.6 | c.1286C>T | p.Pro429Leu | missense_variant | 12/13 | 2 | ENSP00000403041.2 | |||
| SLC6A8 | ENST00000485324.1 | n.1938C>T | non_coding_transcript_exon_variant | 5/6 | 2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 38
GnomAD4 genome
ClinVar
Submissions by phenotype
Creatine transporter deficiency Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 18, 2023 | Variant summary: SLC6A8 c.1631C>T (p.Pro544Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182621 control chromosomes (gnomAD). c.1631C>T has been reported in the literature in multiple hemizygotes affected with Creatine Deficiency, X-Linked (e.g., Mancini_2005, Mancardi_2007, Fons_2008, Comeaux_2013). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced creatine uptake in hemizygous patient fibroblasts (approximately 12% uptake relative to controls at physiological substrate concentrations; Mancini_2005) as well as in vitro (approx. 39% of wild-type levels; Betsalel_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22281021, 23660394, 18925426, 17553121, 15690373). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Oct 26, 2023 | The NM_005629.4:c.1631C>T in SLC6A8 is a missense variant predicted to cause substitution of Proline with Leucine (p.Pro544Leu) at amino acid 544 in the 12th of 13 exons. This variant is absent from gnomAD v2.1.1, (PM2_Supporting). The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). This variant was reported in a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. Urine analysis showed an increased creatine/creatinine ratio (1.83; n.v. 0.03–0.92) with normal guanidinoacetate/creatinine ratio (0.024; n.v. 0.023–0.214) (1 point). Brain MRI with angiography and perfusion study was normal, while 1H-MRS revealed a consistent decrease in the creatine peak (Fig. 2) (3 points). Full sequencing of the SLC6A8 gene was reported. (PMID:17553121) (PP4_Strong). This variant was reported in a proband with an increased urine creatine/creatinine ratio of 2.0 (normal range 0.017–0.72), the proband’s brother also was affected and had elevated urine ratios and was hemizygous for the variant, while their mother was heterozygous for the same variant (PMID: 15690373). (PS4_Supporting). A female proband presented with learning disabilities, seizures and significantly reduced creatine by 1 H-MRS (fig. 1). The patient had normal urine creatine/creatinine ratio (0.38 mmol/mmol). Molecular genetic testing identified the heterozygous variant SLC6A8 (c.1631C>T, p.(Pro544Leu)). Segregation analysis including both parents revealed that the variant was de novo in the patient (PMID: 37708665) (PM6). This variant was assessed for co-segregation evidence (PP1) and functional evidence (PS3), but in both cases did not meet the specifications (PP1_Not Met, PS3_Not Met). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant 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 1.1.0). PM2_Supporting, PP3, PP4_Strong, PS4_Supporting, PM6. (Classification approved by the ClinGen CCDS VCEP on Oct. 26, 2023) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 14, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 544 of the SLC6A8 protein (p.Pro544Leu). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects SLC6A8 function (PMID: 22281021). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC6A8 protein function. ClinVar contains an entry for this variant (Variation ID: 65692). This missense change has been observed in individual(s) with X-linked creatine transporter defect (PMID: 15690373, 17553121, 21556832, 23644449). - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2024 | Published functional studies found this variant is associated with significantly reduced creatine uptake and aberrant protein expression (PMID: 22281021, 30885608); 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: 25861866, 20528887, 23644449, 17553121, 24962355, 23408511, 21556832, 24789340, 24953403, 33192443, 23660394, 37708665, 22281021, 17825809, 18925426, 15690373, 30885608) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at