chrX-153694577-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_StrongPP1_StrongPP4_StrongPM2_Supporting

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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 1.64

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PVS1

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.

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 link	c.1540C>T	p.Arg514*	stop_gained	Exon 11 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1510C>T	p.Arg504*	stop_gained	Exon 11 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1195C>T	p.Arg399*	stop_gained	Exon 11 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.1540C>T	p.Arg514*	stop_gained	Exon 11 of 13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.00000914

AC:

AN:

109403

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31769

show subpopulations

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.:

GnomAD4 genome

AF:

0.00000914

AC:

AN:

109446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31822

show subpopulations

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

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Pathogenic:3

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 13, 2023

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.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

Mar 27, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 06, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over