rs80338739

Positions:

• chrX-153690427-TTTC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_005629.4(SLC6A8):​c.321_323delCTT​(p.Phe107del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC6A8 NM_005629.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:2
• Conservation: PhyloP100: 7.97

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005629.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-153690427-TTTC-T is Pathogenic according to our data. Variant chrX-153690427-TTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 21448.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-153690427-TTTC-T is described in Lovd as [Pathogenic]. Variant chrX-153690427-TTTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	2/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	2/13		NP_001136277.1
SLC6A8	NM_001142806.1	c.-25_-23delCTT		5_prime_UTR_variant	2/13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	2/13	1	NM_005629.4	ENSP00000253122.5
SLC6A8	ENST00000430077	c.-25_-23delCTT		5_prime_UTR_variant	2/13	2		ENSP00000403041.2
SLC6A8	ENST00000476466.1	n.173_175delCTT		non_coding_transcript_exon_variant	2/3	3
SLC6A8	ENST00000675713.1	n.75_77delCTT		non_coding_transcript_exon_variant	1/3

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:6 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:4 Other:2

Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_005629.4(SLC6A8):c.318_320delCTT variant in SLC6A8 is a 3 nucleotide deletion predicted to lead to the in-frame deletion of a single Phenylalanine at amino acid 107 (p.Phe107del). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. Individuals with this variant have been reported in the literature. In deGrauw, 2002 [PMID:12536364] a family with two affected males, one affected female, and one asymptomatic female (mother) were reported. Individual MB from this family was reported with elevated creatine: creatinine in urine, MRS showing absent creatine and phosphocreatine peak, and is used to fulfill PP4_Strong criteria and therefore not used as PS4 evidence. Segregations from this family are used as PP1 evidence. At least 3 additional affected individuals meeting PP4 criteria have been reported [PMID:19188083, 29435807, 33267903], not including the family from deGrauw. Functional studies have been performed, but do not meet the criteria established for PS3 evidence from the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (creatine <125uM creatine used for creatine transport assay) [PMID: 17465020]. There is a ClinVar entry for this variant (Variation ID:21448). In summary, this variant meets the criteria to be classified as a Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS4, PP4_Strong, PM4, PP1_Moderate, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 23, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This variant, c.321_323del, results in the deletion of 1 amino acid(s) of the SLC6A8 protein (p.Phe107del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical and/or biochemical features of creatine transporter deficiency (PMID: 12536364, 12889669, 15154114, 25590979). It has also been observed to segregate with disease in related individuals. This variant is also known as c.316_318delTTC (p.Phe106del). ClinVar contains an entry for this variant (Variation ID: 21448). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC6A8 function (PMID: 17465020). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	-	Variant identified in multiple registry participants. Variant interpreted as Likely pathogenic and reported on 08-25-2017 by lab or GTR ID 61756. Variant reported on 05-01-2014 by lab or GTR ID Amsterdam UMC Metabolic Laboratory. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on creatine uptake (Rosenberg et al., 2007); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 29435807, 34050321, 25590979, 12889669, 12536364, 17465020) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80338739; hg19: chrX-152955882;