NM_005629.4(SLC6A8):c.1171C>T (p.Arg391Trp) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 20, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000623839.4

Allele description [Variation Report for NM_005629.4(SLC6A8):c.1171C>T (p.Arg391Trp)]

NM_005629.4(SLC6A8):c.1171C>T (p.Arg391Trp)

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.1171C>T (p.Arg391Trp)

Other names:

NM_005629.4(SLC6A8):c.1171C>T; p.Arg391Trp

HGVS:

NC_000023.11:g.153693934C>T
NG_012016.2:g.10638C>T
NM_001142805.2:c.1141C>T
NM_001142806.1:c.826C>T
NM_005629.4:c.1171C>TMANE SELECT
NP_001136277.1:p.Arg381Trp
NP_001136278.1:p.Arg276Trp
NP_005620.1:p.Arg391Trp
NC_000023.10:g.152959389C>T
NG_012016.1:g.10638C>T
NM_005629.3:c.1171C>T

Protein change:

R276W

Links:

dbSNP: rs1557045267

NCBI 1000 Genomes Browser:

rs1557045267

Molecular consequence:

NM_001142805.2:c.1141C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142806.1:c.826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005629.4:c.1171C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000741726	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17465020, 21910234, 30885608 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000741726

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application.

Rosenberg EH, Martínez Muñoz C, Betsalel OT, van Dooren SJ, Fernandez M, Jakobs C, deGrauw TJ, Kleefstra T, Schwartz CE, Salomons GS.

Hum Mutat. 2007 Sep;28(9):890-6.

PubMed [citation]

PMID:: 17465020

Creatine transporter defect diagnosed by proton NMR spectroscopy in males with intellectual disability.

Mencarelli MA, Tassini M, Pollazzon M, Vivi A, Calderisi M, Falco M, Fichera M, Monti L, Buoni S, Mari F, Engelke U, Wevers RA, Hayek J, Renieri A.

Am J Med Genet A. 2011 Oct;155A(10):2446-52. doi: 10.1002/ajmg.a.34208. Epub 2011 Sep 9.

PubMed [citation]

PMID:: 21910234
PMCID:: PMC3306553

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000741726.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.1171C>T (p.R391W) alteration is located in exon 8 (coding exon 8) of the SLC6A8 gene. This alteration results from a C to T substitution at nucleotide position 1171, causing the arginine (R) at amino acid position 391 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with SLC6A8-related cerebral creatine deficiency syndrome (Mencarelli, 2011; External communication) This amino acid position is not well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies suggest that overexpression of the p.R391W variant results in deficiency of creatine uptake in SLC6A8 deficient fibroblasts (Rosenberg, 2007; El-Kasaby, 2019). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely 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

Last Updated: Sep 29, 2024

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