rs397515559

Variant names:

• chrX-153694783-C-T
• rs397515559
• NM_005629.4:c.1661C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4_Moderate PP4_Strong PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1661C>T variant in SLC6A8 is predicted to result in the substitution of proline by leucine at amino acid 554 (p.Pro554Leu). This variant has been reported in a hemizygous male with clinical features consistent with creatine transporter deficiency, elevated urine creatine/creatinine ratio, and deficient creatine uptake in fibroblasts (PMID:15690373, 21556832, 24789340) (PP4_Strong). This variant has also been reported in another 4 unrelated probands, all with clinical features consistent with creatine transporter deficiency. Two of these individuals (one male, one female) have biochemical and/or brain magnetic resonance spectroscopy (MRS) data to support the diagnosis (PMID:15154114, 17465020, 21836662; 33164824) (PS4_Moderate). Supportive biochemical, MRS, or creatine uptake results are not available for the other two patients (PMID:23660394, 30293248). One proband has an affected brother, with elevated creatine/creatinine ratio in urine and deficient creatine transport in fibroblasts; their mother is heterozygous for the variant and has mild learning difficulties (PMID:15690373) (2 segregations, PP1_Moderate). Segregation of the clinical symptoms with the variant has been reported in other families, but no biochemical, MRS, or creatine uptake studies were performed in the affected individuals and, therefore, this data will not be counted towards PP1 (PMID:15154114 - 5 segregations; PMID:33164824). The variant is not in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). Overexpression of the variant in SLC6A8-deficient fibroblasts did not result in a significant increase in creatine transport. Studies were carried out with 500uM creatine (PMID:17465020). The CCDS VCEP requires that studies are carried out with <125uM creatine. Therefore, PS3 is not met. The computational predictor REVEL gives a score of 0.937 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variant ID: 65693). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PS4_Moderate, PP1_Moderate, PP3, PM2_Supporting.)Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on Jan 7, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA345036/MONDO:0010305/027

• Frequency: Genomes: not found (cov: 25)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.79
• Publications: 20 publications found

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]

SLC6A8 Gene-Disease associations (from GenCC):

• creatine transporter deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Specifications for SLC6A8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.1661C>T	p.Pro554Leu	missense	Exon 12 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1631C>T	p.Pro544Leu	missense	Exon 12 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1316C>T	p.Pro439Leu	missense	Exon 12 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1661C>T	p.Pro554Leu	missense	Exon 12 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1658C>T	p.Pro553Leu	missense	Exon 12 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1652C>T	p.Pro551Leu	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Creatine transporter deficiency (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.96	D
Vest4		0.98
MutPred		0.93		Gain of catalytic residue at P554 (P = 0.0048)
MVP		0.99
MPC		0.27
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397515559; hg19: chrX-152960238;