NM_005629.4(SLC6A8):c.1145C>T (p.Pro382Leu) AND Creatine transporter deficiency

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Dec 8, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000640931.19

Allele description [Variation Report for NM_005629.4(SLC6A8):c.1145C>T (p.Pro382Leu)]

NM_005629.4(SLC6A8):c.1145C>T (p.Pro382Leu)

Gene:

SLC6A8:solute carrier family 6 member 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_005629.4(SLC6A8):c.1145C>T (p.Pro382Leu)

Other names:

NM_005629.4(SLC6A8):c.1145C>T; p.Pro382Leu

HGVS:

NC_000023.11:g.153693908C>T
NG_012016.2:g.10612C>T
NM_001142805.2:c.1115C>T
NM_001142806.1:c.800C>T
NM_005629.4:c.1145C>TMANE SELECT
NP_001136277.1:p.Pro372Leu
NP_001136278.1:p.Pro267Leu
NP_005620.1:p.Pro382Leu
NC_000023.10:g.152959363C>T
NG_012016.1:g.10612C>T
NM_005629.3:c.1145C>T

Protein change:

P267L

Links:

dbSNP: rs1557045250

NCBI 1000 Genomes Browser:

rs1557045250

Molecular consequence:

NM_001142805.2:c.1115C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142806.1:c.800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005629.4:c.1145C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Creatine transporter deficiency (CCDS1)
Synonyms:: Creatine deficiency, X-linked; Mental retardation , X-linked with seizures, short stature and midface hypoplasia; Mental retardation , X-linked, with creatine transport deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010305; MedGen: C1845862; Orphanet: 52503; OMIM: 300352

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000762535	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 30, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19188083, 22281021, 30885608, 32207963, 28492532
SCV001156348	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	no classification provided	not provided	unknown	phenotyping only
SCV001428483	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 8, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001438321	National Institute of Neuroscience, National Center of Neurology and Psychiatry	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	maternal	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33624935
SCV002764894	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Likely pathogenic (Oct 6, 2021)	germline	clinical testing	Citation Link,
SCV003852669	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen_CCDS_ACMG_Specifications_SLC6A8_v1.1)	Likely pathogenic (Dec 8, 2022)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	maternal	yes	2	not provided	not provided	not provided	not provided	research
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Screening for X-linked creatine transporter (SLC6A8) deficiency via simultaneous determination of urinary creatine to creatinine ratio by tandem mass-spectrometry.

Mercimek-Mahmutoglu S, Muehl A, Salomons GS, Neophytou B, Moeslinger D, Struys E, Bodamer OA, Jakobs C, Stockler-Ipsiroglu S.

Mol Genet Metab. 2009 Apr;96(4):273-5. doi: 10.1016/j.ymgme.2008.12.020. Epub 2009 Feb 1.

PubMed [citation]

PMID:: 19188083

Detection of variants in SLC6A8 and functional analysis of unclassified missense variants.

Betsalel OT, Pop A, Rosenberg EH, Fernandez-Ojeda M; Creatine Transporter Research, Group., Jakobs C, Salomons GS.

Mol Genet Metab. 2012 Apr;105(4):596-601. doi: 10.1016/j.ymgme.2011.12.022. Epub 2012 Jan 6.

PubMed [citation]

PMID:: 22281021

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000762535.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 382 of the SLC6A8 protein (p.Pro382Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of creatine transporter deficiency (PMID: 19188083, 30885608; Invitae). ClinVar contains an entry for this variant (Variation ID: 533700). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC6A8 function (PMID: 22281021, 30885608, 32207963). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies, SCV001156348.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Uncertain significance and reported on 01-03-2018 by GTR ID 500031. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428483.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From National Institute of Neuroscience, National Center of Neurology and Psychiatry, SCV001438321.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764894.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV003852669.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_005629.4:c.1145C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 382 (p.Pro382Leu). This variant is absent from gnomADv2.1.1, and has been reported in two individuals in the literature. In one affected individual in the literature, the ratio of urine Creatine to Creatinine was >99th percentile of normal, and reduced creatine uptake in patient fibroblasts was reported. In silico predictor REVEL suggests this variant will have a damaging / pathogenic effect on the protein (score=0.906). There is a ClinVar entry for this variant (Variation ID: 533700, 1 star review status) with 5 submitters classifying the variant with conflicting interpretations (Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)). In summary, this variant meets the criteria to be classified as Likely 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 1.0): PP4_Strong, PM2_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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