rs122453117

Variant names:

• chrX-153691304-G-T
• rs122453117
• NM_005629.4:c.395G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_Supporting PP3 PP4_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.395G>T variant in SLC6A8 is a missense variant that is predicted to result in the substitution of a glycine for a valine at amino acid 132 (p.Gly132Val). This variant has been previously reported one hemizygous male (PMID:17101918, PMID:23644449) who had elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID:17101918) (PP4_Strong). This variant was reported to result in <10% creatine transport activity when expressed in SLC6A8-deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID:22281021, 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.916 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 (Variation ID: 2290132). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. ACMG/AMP SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256014/MONDO:0010305/027

• Frequency: Genomes: not found (cov: 25)
• Consequence: SLC6A8 NM_005629.4 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.99

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 7 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.
• 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 rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.395G>T	p.Gly132Val	missense_variant, splice_region_variant	Exon 3 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.395G>T	p.Gly132Val	missense_variant, splice_region_variant	Exon 3 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.50G>T	p.Gly17Val	missense_variant, splice_region_variant	Exon 3 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.395G>T	p.Gly132Val	missense_variant, splice_region_variant	Exon 3 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 25

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:2

Nov 14, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 11, 2024

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:c.395G>T variant in SLC6A8 is a missense variant that is predicted to result in the substitution of a glycine for a valine at amino acid 132 (p.Gly132Val). This variant has been previously reported one hemizygous male (PMID: 17101918, PMID: 23644449) who had elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 17101918) (PP4_Strong). This variant was reported to result in <10% creatine transport activity when expressed in SLC6A8-deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID: 22281021, 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.916 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 (Variation ID: 2290132). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. ACMG/AMP SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on April 11, 2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.4	H;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.95		Gain of ubiquitination at K131 (P = 0.0693);.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.14		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: rs122453117; hg19: chrX-152956759;