rs1557045267

Variant names:

• chrX-153693934-C-T
• rs1557045267
• NM_005629.4:c.1171C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 5 ACMG points: 6P and 1B. PS3_Supporting PP4_Strong PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4(SLC6A8):c.1171C>T (p.Arg391Trp) variant in SLC6A8 is a missense variant predicted to cause substitution of Tryptophan for Arginine at amino acid 391 (p.Arg391Trp). There is a ClinVar entry for this variant (Variation ID:465141, Conflicting Interpretations) with classifications as Pathogenic (n=2) and as a Variant of Uncertain Significance (n=1). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.078 which is below the threshold of 0.20, suggesting a benign effect of this variant on protein function, therefore BP4 criteria is applicable. The p.Arg391Trp variant has been reported in a male with intellectual disability, speech delay, and seizures who had biochemical studies including elevated Creatine:Creatinine ratio in urine and MRS demonstrating reduced Creatine peak in brain (Patient 2; [PMID:21910234]), which meets criteria for PP4_Strong. The patient from Mencarelli, 2011 [PMID:21910234] was also found to have the c.1171C>T (p.Arg391Trp) variant de novo, meeting criteria for PS2. Site directed mutagenesis and creatine uptake studies were performed with the p.Arg391Trp variant, and these studies demonstrated creatine uptake <10% wildtype cells (<150 μM creatine used), meeting PS3_Supporting criteria [PMID:30885608]. This variant has also been identified in a male with intellectual disability and/or seizures but without biochemical evidence of creatine transporter deficiency (elevated urine creatine:creatine, MRS demonstrating reduced creatine peak) [PMID:16738945], and given the absence of biochemical evidence of Creatine Transporter Deficiency in this individual evidence for pathogenicity was not scored. 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 1.1.0): PP4_Strong, PS2, PS3_Supporting, PM2_Supporting, BP4. Classification changed from VUS to LP given the only benign/conflicting evidence for this variant is in silico evidence. Using the new point scoring system from Tavtigian et.al 2020 [PMID:32720330], this variant meets criteria for Likely Pathogenic (Score: 4+4+1+1-1 = 9 points; Likely Pathogenic).(Classification approved by the CCDS VCEP Nov 10, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA415086241/MONDO:0010305/027

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.239

Genes affected

SLC6A8 (HGNC:11055): (solute carrier family 6 member 8) The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1171C>T	p.Arg391Trp	missense_variant	Exon 8 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1141C>T	p.Arg381Trp	missense_variant	Exon 8 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.826C>T	p.Arg276Trp	missense_variant	Exon 8 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1171C>T	p.Arg391Trp	missense_variant	Exon 8 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1056214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 343906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:4

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 391 of the SLC6A8 protein (p.Arg391Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with creatine transporter deficiency (PMID: 16738945, 21910234; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 465141). 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. Experimental studies have shown that this missense change affects SLC6A8 function (PMID: 17465020). For these reasons, this variant has been classified as Pathogenic. -

Nov 10, 2022

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_005629.4(SLC6A8):c.1171C>T (p.Arg391Trp) variant in SLC6A8 is a missense variant predicted to cause substitution of Tryptophan for Arginine at amino acid 391 (p.Arg391Trp). There is a ClinVar entry for this variant (Variation ID:465141, Conflicting Interpretations) with classifications as Pathogenic (n=2) and as a Variant of Uncertain Significance (n=1). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.078 which is below the threshold of 0.20, suggesting a benign effect of this variant on protein function, therefore BP4 criteria is applicable. The p.Arg391Trp variant has been reported in a male with intellectual disability, speech delay, and seizures who had biochemical studies including elevated Creatine:Creatinine ratio in urine and MRS demonstrating reduced Creatine peak in brain (Patient 2; [PMID:21910234]), which meets criteria for PP4_Strong. The patient from Mencarelli, 2011 [PMID:21910234] was also found to have the c.1171C>T (p.Arg391Trp) variant de novo, meeting criteria for PS2. Site directed mutagenesis and creatine uptake studies were performed with the p.Arg391Trp variant, and these studies demonstrated creatine uptake <10% wildtype cells (<150 μM creatine used), meeting PS3_Supporting criteria [PMID:30885608]. This variant has also been identified in a male with intellectual disability and/or seizures but without biochemical evidence of creatine transporter deficiency (elevated urine creatine:creatine, MRS demonstrating reduced creatine peak) [PMID:16738945], and given the absence of biochemical evidence of Creatine Transporter Deficiency in this individual evidence for pathogenicity was not scored. 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 1.1.0): PP4_Strong, PS2, PS3_Supporting, PM2_Supporting, BP4. Classification changed from VUS to LP given the only benign/conflicting evidence for this variant is in silico evidence. Using the new point scoring system from Tavtigian et.al 2020 [PMID:32720330], this variant meets criteria for Likely Pathogenic (Score: 4+4+1+1-1 = 9 points; Likely Pathogenic). (Classification approved by the CCDS VCEP Nov 10, 2022) -

Mar 22, 2023

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Molecular Genetics Lab, CHRU Brest

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Nov 20, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1171C>T (p.R391W) alteration is located in exon 8 (coding exon 8) of the SLC6A8 gene. This alteration results from a C to T substitution at nucleotide position 1171, causing the arginine (R) at amino acid position 391 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with SLC6A8-related cerebral creatine deficiency syndrome (Mencarelli, 2011; External communication) This amino acid position is not well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies suggest that overexpression of the p.R391W variant results in deficiency of creatine uptake in SLC6A8 deficient fibroblasts (Rosenberg, 2007; El-Kasaby, 2019). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Oct 30, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30885608, 27081545, 15154114, 28065824, 15234334, 24190795, 10893433, 20846889, 23644449, 20528887, 21910234, 23408511, 16738945, 17465020, 24137762) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	21
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.49	N
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.16	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.078
MutPred		0.16		Loss of relative solvent accessibility (P = 0.008);
MVP		0.94
ClinPred		0.99	D
GERP RS		0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557045267; hg19: chrX-152959389;