NM_005629.4(SLC6A8):c.145G>C (p.Val49Leu) AND Creatine transporter deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 6, 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:: RCV000815145.6

Allele description [Variation Report for NM_005629.4(SLC6A8):c.145G>C (p.Val49Leu)]

NM_005629.4(SLC6A8):c.145G>C (p.Val49Leu)

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.145G>C (p.Val49Leu)

Other names:

NM_005629.4(SLC6A8):c.145G>C; p.Val49Leu

HGVS:

NC_000023.11:g.153688719G>C
NG_012016.2:g.5423G>C
NM_001142805.2:c.145G>C
NM_005629.4:c.145G>CMANE SELECT
NP_001136277.1:p.Val49Leu
NP_005620.1:p.Val49Leu
NC_000023.10:g.152954174G>C
NG_012016.1:g.5423G>C
NM_005629.3:c.145G>C

Protein change:

V49L

Links:

dbSNP: rs1463935788

NCBI 1000 Genomes Browser:

rs1463935788

Molecular consequence:

NM_001142805.2:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005629.4:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000955591	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002600173	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen_CCDS_ACMG_Specifications_SLC6A8_v1.1)	Uncertain significance (Jun 6, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000955591

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 24, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002600173

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen_CCDS_ACMG_Specifications_SLC6A8_v1.1)

Uncertain significance
(Jun 6, 2022)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000955591.2

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

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV002600173.1

#	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(SLC6A8):c.145G>C (p.Val49Leu) variant in SLC6A8 is a missense variant predicted to cause substitution of Valine for Leucine at amino acid 49 (p.Val49Leu). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.032 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI does no predict an impact on splicing (BP4). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:658337). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance 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): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

#	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: Sep 29, 2024

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