rs397515558

Variant names:

• chrX-153694753-C-T
• rs397515558
• NM_005629.4:c.1631C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4_Strong PM6 PP3 PM2_Supporting PS4_Supporting

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: Genomes: not found (cov: 25)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 4.82
• Publications: 0 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

Our verdict: Likely_pathogenic. The variant received 9 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.
• PM6: 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.1631C>T	p.Pro544Leu	missense	Exon 12 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1601C>T	p.Pro534Leu	missense	Exon 12 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1286C>T	p.Pro429Leu	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.1631C>T	p.Pro544Leu	missense	Exon 12 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1628C>T	p.Pro543Leu	missense	Exon 12 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1622C>T	p.Pro541Leu	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.89		Loss of helix (P = 0.1299)
MVP		0.80
MPC		0.61
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.89
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: rs397515558; hg19: chrX-152960208; COSMIC: COSV53472107; COSMIC: COSV53472107;