rs121908173
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_030777.4(SLC2A10):c.394C>T(p.Arg132Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,986 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_030777.4 missense
Scores
Clinical Significance
Conservation
Publications
- arterial tortuosity syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_030777.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SLC2A10 | NM_030777.4 | MANE Select | c.394C>T | p.Arg132Trp | missense | Exon 2 of 5 | NP_110404.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SLC2A10 | ENST00000359271.4 | TSL:1 MANE Select | c.394C>T | p.Arg132Trp | missense | Exon 2 of 5 | ENSP00000352216.2 | ||
| SLC2A10 | ENST00000611837.1 | TSL:2 | n.546C>T | non_coding_transcript_exon | Exon 2 of 2 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152142Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000318 AC: 8AN: 251318 AF XY: 0.0000368 show subpopulations
GnomAD4 exome AF: 0.0000527 AC: 77AN: 1461844Hom.: 0 Cov.: 33 AF XY: 0.0000509 AC XY: 37AN XY: 727226 show subpopulations
Age Distribution
GnomAD4 genome 0.0000920 AC: 14AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74318 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Arterial tortuosity syndrome Pathogenic:8Uncertain:1Other:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 132 of the SLC2A10 protein (p.Arg132Trp). This variant is present in population databases (rs121908173, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive arterial tortuosity syndrome (PMID: 17935213, 28726533, 29543232). 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: 4590). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC2A10 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
SLC2A10 NM_030777.3 exon 2 p.Arg132Trp (c.394C>T): This variant has been reported in the literature in the compound heterozygous state with another pathogenic variant, in at least 5 individuals with aterial tortuosity syndrome, segregating with disease in one affected family member (Callewaert 2008 PMID:17935213, Hardin 2018 PMID:28726533, Weerakkody 2018 PMID:29543232). This variant is present in 0.005% (7/129070) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/20-45354069-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:4590). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
We are submitting the c.394C>T variant in the SLC2A10 gene, located in exon 2, which results in the p.Arg132Trp amino acid substitution. This missense variant is suspected to cause a change in protein function, potentially disrupting the normal function of the SLC2A10 protein. The variant has been previously described in the literature (PMID 17935213 and 29323665) and classified as likely pathogenic or pathogenic in ClinVar. Based on the clinical and molecular evidence in our study, we are submitting this variant again as pathogenic. Supporting Evidence for Classification: We assigned the following criteria to this variant: PP3: In silico predictions suggest that the p.Arg132Trp substitution may significantly impact protein function. The REVEL score of 0.855 further supports this, indicating a moderate to high probability that this variant is deleterious. This strengthens the hypothesis that the variant could disrupt the normal structure and function of the SLC2A10 protein. PP4: The patients in our study, who are compound heterozygous for the c.394C>T variant and another pathogenic SLC2A10 variant, exhibits clinical features consistent with ATS. PP5: The variant has been previously reported as likely pathogenic or pathogenic in multiple studies (PMID 17935213 and PMID 29323665), strengthening its association with ATS. PM1: The p.Arg132Trp substitution occurs in a highly conserved amino acid residue, suggesting that changes at this position could have significant functional consequences for the SLC2A10 protein. The conservation across species supports the pathogenic potential of this variant. PM2: The variant is rare in the general population, with a minor allele frequency (MAF) of 5.27E-05 in gnomAD, consistent with the rarity expected for pathogenic variants in SLC2A10-related disorders. The low allele frequency supports the pathogenicity of this variant. PM3: The patients are compound heterozygous for the c.394C>T variant with other suspected pathogenic SLC2A10 variants. PM5: Functional studies or additional evidence may be required to conclusively demonstrate the impact of this specific missense substitution on the SLC2A10 protein. However, the combination of the other criteria and clinical findings supports the pathogenic classification of this variant. In conclusion, the c.394C>T (p.Arg132Trp) variant in SLC2A10 is classified as pathogenic, based on strong clinical, molecular, and computational evidence.
Variant summary: SLC2A10 c.394C>T (p.Arg132Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251318 control chromosomes (gnomAD). c.394C>T has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Arterial Tortuosity Syndrome and has been found to segregate with the disease phenotype in at least one family (e.g. Beyens_2018, Callewaert_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29323665, 17935213). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1)/likely pathogenic (n=3) and VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arterial tortuosity syndrome (MIM#208050). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability also reported (PMID: 30425910). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 18 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sugar (and other) transporter domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Arg132Leu)) has been reported once as likely pathogenic (ClinVar). Another variant (p.(Arg132Gln)) has been reported in a homozygous and a compound heterozygous individual with arterial tortuosity syndrome (ATS), but also described as a VUS and as likely pathogenic (ClinVar, PMID: 29323665). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice as a VUS, but more recently as likely pathogenic and pathogenic, and has been observed in at least six unrelated compound heterozygous individuals with ATS (PMID: 29323665, PMID: 17935213, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
The p.Arg132Trp variant in SLC2A10 has been reported in the compound heterozygous state with another pathogenic variant in at least 5 individuals with features of arterial tortuosity syndrome and segregated with disease in one relative(Callewaert 2008 PMID:17935213, Hardin 2018 PMID:28726533, Weerakkody 2018 PMID:29543232, Beyens 2018 PMID: 29323665). It has also been reported in ClinVar (Variation ID:4590). This variant has been identified in 11/68012 of European alleles by gnomAD (https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive arterial tortuosity syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3_VS.
not provided Pathogenic:4
SLC2A10: PM3:Very Strong, PM2, PM5:Supporting
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25392904, 17935213, 29543232, 28726533, 39456956, 29323665)
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
The p.R132W pathogenic mutation (also known as c.394C>T), located in coding exon 2 of the SLC2A10 gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported to co-occur in trans with other pathogenic variants in the SLC2A10 gene in probands with arterial tortuosity syndrome (Callewaert BL et al, Hum. Mutat. 2008 Jan; 29(1):150-8; Beyens A et al. Genet Med. 2018 Oct;20(10):1236-1245). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at