rs1060502808

Variant names:

• chrX-153693321-TCA-T
• rs1060502808
• NM_005629.4:c.974_975delCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005629.4(SLC6A8):​c.974_975delCA​(p.Thr325SerfsTer139) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T325T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC6A8 NM_005629.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 5.98
• Publications: 3 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153693321-TCA-T is Pathogenic according to our data. Variant chrX-153693321-TCA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 410218.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.974_975delCA	p.Thr325SerfsTer139	frameshift_variant	Exon 6 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.974_975delCA	p.Thr325SerfsTer129	frameshift_variant	Exon 6 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.629_630delCA	p.Thr210SerfsTer139	frameshift_variant	Exon 6 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.974_975delCA	p.Thr325SerfsTer139	frameshift_variant	Exon 6 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:3

May 02, 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.972_973del (p.Thr325SerfsTer139) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two maternal half-brothers have been reported to be hemizygous for the variant, both with clinical features consistent with creatine transporter deficiency, markedly reduced creatine level on brain MRS, elevated urine creatine/creatinine ratio, and <3% transporter activity in fibroblasts (PMID 20602486) (PP4_Strong). This variant is not in gnomAD v2.1.1. or v4.1.0 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 410218). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on May 2, 2024) -

Apr 18, 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: 410218). This premature translational stop signal has been observed in individual(s) with X-linked cerebral creatine deficiency (PMID: 20602486). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr325Serfs*139) 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). -

Oct 04, 2019

Institute of Human Genetics Munich, TUM 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
PhyloP100		6.0
BranchPoint Hunter		8.0
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1060502808; hg19: chrX-152958776;