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

gnomAD frequency: 0.00002  dbSNP: rs771028960

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251075	SCV000319257	pathogenic	Cardiovascular phenotype	2014-03-27	criteria provided, single submitter	clinical testing	The p.R231Q pathogenic mutation (also known as c.692G>A), located in coding exon 2 of the SLC2A10 gene in the endofacial loop between two transmembrane domains, results from a G to A substitution at nucleotide position 692. The arginine at codon 231 is replaced by glutamine. This amino acid position is highly conserved on sequence alignment. This alteration was originally reported in a Spanish family in trans with a frameshift mutation in three affected siblings (Callewaert BL et al. Hum Mutat. 2008;29(1):150-158). In another study, p.R231Q was reported in a Japanese patient in trans with a nonsense mutation (Takahashi Y et al. Am J Med Genet A. 2013;161A(4):856-859). Another alteration of the same codon, p.R231W (c.691C>T), was reported in trans with a frameshift mutation in an Italian family (Ritelli M et al. Orphanet J Rare Dis. 2009;4:20). Based on the supporting evidence, p.R231Q is interpreted as a disease-causing mutation.
Illumina Laboratory Services, Illumina	RCV000185549	SCV000914960	uncertain significance	Arterial tortuosity syndrome	2017-05-09	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000185549	SCV004336418	pathogenic	Arterial tortuosity syndrome	2023-12-17	criteria provided, single submitter	clinical testing	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.
GeneReviews	RCV000185549	SCV000195649	not provided	Arterial tortuosity syndrome		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185549	SCV000238431	likely pathogenic	Arterial tortuosity syndrome	2015-04-01	no assertion criteria provided	research	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).