X-153694783-C-T

Position:

• chrX-153694783-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_005629.4(SLC6A8):​c.1661C>T​(p.Pro554Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.79

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-153694783-C-T is Pathogenic according to our data. Variant chrX-153694783-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153694783-C-T is described in Lovd as [Pathogenic]. Variant chrX-153694783-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1661C>T	p.Pro554Leu	missense_variant	12/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1631C>T	p.Pro544Leu	missense_variant	12/13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1316C>T	p.Pro439Leu	missense_variant	12/13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1661C>T	p.Pro554Leu	missense_variant	12/13	1	NM_005629.4	ENSP00000253122	P1
SLC6A8	ENST00000430077.6	c.1316C>T	p.Pro439Leu	missense_variant	12/13	2		ENSP00000403041
SLC6A8	ENST00000485324.1	n.1968C>T		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Creatine transporter deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2022	This missense change has been observed in individuals with creatine transporter deficiency and X-linked mental retardation due to SLC6A8-deficiency (PMID: 15154114, 21836662, 23660394, 25803912). It has also been observed to segregate with disease in related individuals. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 554 of the SLC6A8 protein (p.Pro554Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 65693). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC6A8 protein function. Experimental studies have shown that this missense change affects SLC6A8 function (PMID: 17465020). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2024

Published functional studies demonstrate significantly reduced creatine uptake activity (PMID: 17465020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33164824, 17465020, 22281021, 25803912, 23408511, 15154114) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.96	D;.
Vest4		0.98
MutPred		0.93		Gain of catalytic residue at P554 (P = 0.0048);.;
MVP		0.99
MPC		0.27
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.98

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: rs397515559; hg19: chrX-152960238;