NM_030777.4(SLC2A10):c.692G>A (p.Arg231Gln) AND Arterial tortuosity syndrome

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Aug 13, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000185549.19

Allele description [Variation Report for NM_030777.4(SLC2A10):c.692G>A (p.Arg231Gln)]

NM_030777.4(SLC2A10):c.692G>A (p.Arg231Gln)

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.692G>A (p.Arg231Gln)

HGVS:

NC_000020.11:g.46725728G>A
NG_016284.1:g.21089G>A
NM_030777.4:c.692G>AMANE SELECT
NP_110404.1:p.Arg231Gln
NP_110404.1:p.Arg231Gln
NC_000020.10:g.45354367G>A
NM_030777.3:c.692G>A
O95528:p.Arg231Gln

Protein change:

R231Q

Links:

UniProtKB: O95528#VAR_042420; dbSNP: rs771028960

NCBI 1000 Genomes Browser:

rs771028960

Molecular consequence:

NM_030777.4:c.692G>A - 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
SCV000195649	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17935213, 23494979
SCV000238431	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (Apr 1, 2015)	germline	research	PubMed (2) [See all records that cite these PMIDs] 17935213, 23494979
SCV000914960	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (May 9, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23494979, 17935213 Citation Link,
SCV004336418	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17935213, 19781076, 28492532
SCV005381161	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 13, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29323665, 17935213, 23494979 Citation Link

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Summary from all submissions

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

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

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

See all PubMed Citations (5)

Details of each submission

From GeneReviews, SCV000195649.2

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

#	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 Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000238431.1

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

Description

This patient is a carrier of a heterozygous likely pathogenic variant in the SLC2A10 gene implicated in causing arterial tortuosity syndrome (MIM 208050). The SLC2A10 variant (c.692G>A) was identified in several patients and segregated in a family with marked carotid artery pulsations and dysmorphic features (Callewaert et al. 2008, PMID: 17935213; Takahashi e al. 2012, PMID: 23494979).

#	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 Illumina Laboratory Services, Illumina, SCV000914960.1

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

Description

The SLC2A10 c.692G>A (p.Arg231Gln) variant has been reported in two studies in which it is found in a total of two patients in a compound heterozygous state with either a deletion or a stop-gained variant as the second allele (Callewaert et al. 2008; Takahashi et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.0000145 in the total population of the Genome Aggregation Database. The evidence for this variant is limited. The c.692G>A (p.Arg231Gln) variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for arterial tortuosity syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004336418.1

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 231 of the SLC2A10 protein (p.Arg231Gln). This variant is present in population databases (rs771028960, gnomAD 0.004%). This missense change has been observed in individual(s) with arterial tortuosity syndrome (PMID: 17935213). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 161097). 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 observed in individuals with SLC2A10-related conditions (PMID: 19781076), which suggests that this may be a clinically significant amino acid residue. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005381161.1

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

Description

Variant summary: SLC2A10 c.692G>A (p.Arg231Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250976 control chromosomes (gnomAD). c.692G>A has been reported in the literature in multiple individuals affected with Arterial Tortuosity Syndrome (e.g. Callewaert_2008, Takahashi_2013, Beyens_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17935213, 29323665, 23494979). ClinVar contains an entry for this variant (Variation ID: 161097). Based on the evidence outlined above, the variant was 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

Last Updated: Nov 10, 2024

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