rs122453114

Variant names:

• chrX-153693586-G-C
• rs122453114
• NM_005629.4:c.1141G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1_Strong PP4_Strong PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1141G>C variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a glycine for an arginine at amino acid 381 (p.Gly381Arg). This variant has been previously reported in one family with 5 affected males with elevated urinary creatine/creatinine and deficient creatine uptake in cultured fibroblasts (PP4_Strong) and segregated with disease in this family (PP1_Strong) (PMID:11898126). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts (PMID:22281021) (PS3_Supporting). In addition, the variant was shown to result in altered splicing via RT-PCR analysis (PMID:11898126). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.923 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 11697, zero-star review status), with one submitter classifying the variant as pathogenic. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP1_Strong, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA256011/MONDO:0010305/027

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC6A8 NM_005629.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.83
• Publications: 6 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, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 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.
• 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 rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1141G>C	p.Gly381Arg	missense_variant, splice_region_variant	Exon 7 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1111G>C	p.Gly371Arg	missense_variant, splice_region_variant	Exon 7 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.796G>C	p.Gly266Arg	missense_variant, splice_region_variant	Exon 7 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1141G>C	p.Gly381Arg	missense_variant, splice_region_variant	Exon 7 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:2

Mar 28, 2024

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_005629.4:c.1141G>C variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a glycine for an arginine at amino acid 381 (p.Gly381Arg). This variant has been previously reported in one family with 5 affected males with elevated urinary creatine/creatinine and deficient creatine uptake in cultured fibroblasts (PP4_Strong) and segregated with disease in this family (PP1_Strong) (PMID: 11898126). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 22281021) (PS3_Supporting). In addition, the variant was shown to result in altered splicing via RT-PCR analysis (PMID: 11898126). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.923 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 11697, zero-star review status), with one submitter classifying the variant as pathogenic. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP1_Strong, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). -

May 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.4	H;.
PhyloP100		9.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.77		Gain of solvent accessibility (P = 0.0789);.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.98
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		Position offset: -13
DS_DL_spliceai		0.27		Position offset: 0

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

Other links and lift over

dbSNP: rs122453114; hg19: chrX-152959041;