rs397515559

Positions:

• chrX-153694783-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PS4_Moderate PP1_Moderate PP4_Strong

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 criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.79

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1661C>T	p.Pro554Leu	missense_variant	12/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1631C>T	p.Pro544Leu	missense_variant	12/13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1316C>T	p.Pro439Leu	missense_variant	12/13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1661C>T	p.Pro554Leu	missense_variant	12/13	1	NM_005629.4	ENSP00000253122.5
SLC6A8	ENST00000430077.6	c.1316C>T	p.Pro439Leu	missense_variant	12/13	2		ENSP00000403041.2
SLC6A8	ENST00000485324.1	n.1968C>T		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Creatine transporter deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2022	This missense change has been observed in individuals with creatine transporter deficiency and X-linked mental retardation due to SLC6A8-deficiency (PMID: 15154114, 21836662, 23660394, 25803912). It has also been observed to segregate with disease in related individuals. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 554 of the SLC6A8 protein (p.Pro554Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 65693). 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. Experimental studies have shown that this missense change affects SLC6A8 function (PMID: 17465020). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2024

Published functional studies demonstrate significantly reduced creatine uptake activity (PMID: 17465020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33164824, 17465020, 22281021, 25803912, 23408511, 15154114) -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515559; hg19: chrX-152960238;