NM_030777.4(SLC2A10):c.691C>T (p.Arg231Trp) AND Arterial tortuosity syndrome

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000202453.30

Allele description [Variation Report for NM_030777.4(SLC2A10):c.691C>T (p.Arg231Trp)]

NM_030777.4(SLC2A10):c.691C>T (p.Arg231Trp)

Gene:

SLC2A10:solute carrier family 2 member 10 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_030777.4(SLC2A10):c.691C>T (p.Arg231Trp)

Other names:

p.R231W:CGG>TGG

HGVS:

NC_000020.11:g.46725727C>T
NG_016284.1:g.21088C>T
NM_030777.4:c.691C>TMANE SELECT
NP_110404.1:p.Arg231Trp
NP_110404.1:p.Arg231Trp
NC_000020.10:g.45354366C>T
NM_030777.3:c.691C>T

Protein change:

R231W

Links:

dbSNP: rs146579504

NCBI 1000 Genomes Browser:

rs146579504

Molecular consequence:

NM_030777.4:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Arterial tortuosity syndrome (ATORS)
Identifiers:: MONDO: MONDO:0008818; MedGen: C1859726; Orphanet: 3342; OMIM: 208050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195661	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000884528	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Jul 9, 2018)	germline	clinical testing	Citation Link,
SCV000933700	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19781076, 34498425, 17935213, 23494979, 28492532
SCV001423273	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV002023547	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 19, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

Arterial tortuosity syndrome in two Italian paediatric patients.

Ritelli M, Drera B, Vicchio M, Puppini G, Biban P, Pilati M, Prioli MA, Barlati S, Colombi M.

Orphanet J Rare Dis. 2009 Sep 25;4:20. doi: 10.1186/1750-1172-4-20.

PubMed [citation]

PMID:: 19781076
PMCID:: PMC2759904

Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China.

Li J, Yang L, Diao Y, Zhou L, Xin Y, Jiang L, Li R, Wang J, Duan W, Liu J.

Mol Genet Genomic Med. 2021 Oct;9(10):e1800. doi: 10.1002/mgg3.1800. Epub 2021 Sep 8.

PubMed [citation]

PMID:: 34498425
PMCID:: PMC8580079

See all PubMed Citations (6)

Details of each submission

From GeneReviews, SCV000195661.2

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000884528.2

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

Description

The SLC2A10 c.691C>T; p.Arg231Trp variant (rs146579504) has been described in the compound heterozygous state in individuals affected with arterial tortuosity syndrome (ATS) (Beyens 2018, Ritelli 2009). It is reported as pathogenic in ClinVar (Variation ID: 161106) and observed in the general population at a low overall frequency of 0.002% (6/276720 alleles) in the Genome Aggregation Database. The arginine at codon 231 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant is damaging. Additionally, another variant at this position (c.692G>A; p.Arg231Gln) has been described in individuals with ATS and is considered pathogenic (Beyens 2018, Callewaert 2008). Based on available information, this variant is considered likely pathogenic. Pathogenic SLC2A10 variants are inherited in an autosomal recessive manner, and are associated with arterial tortuosity syndrome (ATS) (MIM: 208050) characterized by tortuosity and elongation of the large and medium-sized arteries, predisposition to aneurysms, vascular dissection, and pulmonary arteries stenosis as well as cutaneous, skeletal and other symptoms. This individual appears to be only a carrier of ATS. However, our analysis cannot detect variants in deep intronic or enhancer regions; therefore, the presence of additional pathogenic variants in these regions cannot be excluded. If an additional pathogenic variant, not detected by the current assay, is present on the opposite chromosome, this individual may be affected with ATS. References: Beyens A et al. Arterial tortuosity syndrome: 40 new families and literature review. Genet Med. 2018 Jan 11. Callewaert B et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008 Jan;29(1):150-8. Ritelli M et al. Arterial tortuosity syndrome in two Italian paediatric patients. Orphanet J Rare Dis. 2009 Sep 25;4:20.

#	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 Invitae, SCV000933700.6

#	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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 231 of the SLC2A10 protein (p.Arg231Trp). This variant is present in population databases (rs146579504, gnomAD 0.004%). This missense change has been observed in individual(s) with aortopathy and/or arterial tortuosity syndrome (PMID: 19781076, 34498425). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 161106). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC2A10 protein function. This variant disrupts the p.Arg231 amino acid residue in SLC2A10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17935213, 23494979). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, ClinGen, SCV001423273.1

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

Description

Variant interpretted as Likely pathogenic and reported on 05-29-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of 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 Revvity Omics, Revvity, SCV002023547.3

#	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

Last Updated: May 12, 2024

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