20-46725728-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_030777.4(SLC2A10):c.692G>A(p.Arg231Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R231W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_030777.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC2A10 | NM_030777.4 | c.692G>A | p.Arg231Gln | missense_variant | 2/5 | ENST00000359271.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC2A10 | ENST00000359271.4 | c.692G>A | p.Arg231Gln | missense_variant | 2/5 | 1 | NM_030777.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250976Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135694
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461812Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727202
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Arterial tortuosity syndrome Pathogenic:2Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 09, 2017 | 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. - |
Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Apr 01, 2015 | 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). - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | 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. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2014 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at