rs122453113

Positions:

• chrX-153694577-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PVS1_Strong PP1_Strong PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1540C>T (p.Arg514Ter) variant in SLC6A8 is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant-exon 11/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). A male patient has been reported with almost complete absence of the creatine signal on brain MRS, elevated creatine in urine, and virtually undetectable creatine transport in fibroblasts (PMID:11326334) (PP4_Strong). The mother, maternal aunt, and maternal grandmother are all heterozygous for the variant and all have evidence of creatine transporter deficiency. The paternal uncle has severe intellectual disability but was unavailable for study (PMID:11326334) (PP1_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral creatine Deficiencies Variant Curation Expert Panel CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP1_Strong, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Oct. 13, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256009/MONDO:0010305/027

• Frequency: Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 22)
• Consequence: SLC6A8 NM_005629.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 1.64

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 Pathogenic. Variant got 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1540C>T	p.Arg514Ter	stop_gained	11/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.1510C>T	p.Arg504Ter	stop_gained	11/13
SLC6A8	NM_001142806.1	c.1195C>T	p.Arg399Ter	stop_gained	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1540C>T	p.Arg514Ter	stop_gained	11/13	1	NM_005629.4	P1
SLC6A8	ENST00000430077.6	c.1195C>T	p.Arg399Ter	stop_gained	11/13	2
SLC6A8	ENST00000485324.1	n.1847C>T		non_coding_transcript_exon_variant	4/6	2
SLC6A8	ENST00000413787.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000914 AC: 1 AN: 109403 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31769

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000914 AC: 1 AN: 109446 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31822

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11696). This premature translational stop signal has been observed in individual(s) with creatine transporter deficiency (PMID: 11326334, 12536364). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg514*) in the SLC6A8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A8 are known to be pathogenic (PMID: 22281021). -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Oct 13, 2023	The NM_005629.4:c.1540C>T (p.Arg514Ter) variant in SLC6A8 is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant-exon 11/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). A male patient has been reported with almost complete absence of the creatine signal on brain MRS, elevated creatine in urine, and virtually undetectable creatine transport in fibroblasts (PMID: 11326334) (PP4_Strong). The mother, maternal aunt, and maternal grandmother are all heterozygous for the variant and all have evidence of creatine transporter deficiency. The paternal uncle has severe intellectual disability but was unavailable for study (PMID: 11326334) (PP1_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral creatine Deficiencies Variant Curation Expert Panel CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP1_Strong, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct. 13, 2023) -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16738945, 34800434, 11326334, 27081545, 24137762, 20528887, 23644449, 20846889, 10893433, 24190795, 15234334, 28065824, 16143026, 12536364, 12544242, 16763899, 15154114, 31031587) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2018

The p.R514* pathogenic mutation (also known as c.1540C>T), located in coding exon 11 of the SLC6A8 gene, results from a C to T substitution at nucleotide position 1540. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation was detected in a male individual with creatine-deficiency syndrome as well as in two of his female relatives with mild biochemical abnormalities and learning disabilities (Salomons GS et al. Am. J. Hum. Genet., 2001 Jun;68:1497-500). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A
Vest4		0.93
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs122453113; hg19: chrX-152960032;