chr20-46725430-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_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 (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

SLC2A10
NM_030777.4 missense

Scores

13
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:1O:1

Conservation

PhyloP100: 1.03
Variant links:
Genes affected
SLC2A10 (HGNC:13444): (solute carrier family 2 member 10) This gene encodes a member of the class III facilitative glucose transporter family. The encoded protein plays a role in regulation of glucose homeostasis. Mutations in this gene have been associated with arterial tortuosity syndrome.[provided by RefSeq, Dec 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 20-46725430-C-T is Pathogenic according to our data. Variant chr20-46725430-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46725430-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC2A10NM_030777.4 linkc.394C>T p.Arg132Trp missense_variant Exon 2 of 5 ENST00000359271.4 NP_110404.1 O95528

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC2A10ENST00000359271.4 linkc.394C>T p.Arg132Trp missense_variant Exon 2 of 5 1 NM_030777.4 ENSP00000352216.2 O95528
SLC2A10ENST00000611837.1 linkn.546C>T non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152142
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251318
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000527
AC:
77
AN:
1461844
Hom.:
0
Cov.:
33
AF XY:
0.0000509
AC XY:
37
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000558
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152142
Hom.:
0
Cov.:
33
AF XY:
0.0000942
AC XY:
7
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000988
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arterial tortuosity syndrome Pathogenic:7Uncertain:1Other:1
Mar 30, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 01, 2008
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Nov 03, 2022
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Nov 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 02, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Apr 26, 2024
Institute of Human Genetics, Heidelberg University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

not provided Pathogenic:4
May 20, 2021
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 4590; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29543232, 17935213, 28726533, 25392904) -

Feb 17, 2022
AiLife Diagnostics, AiLife Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SLC2A10: PM3:Very Strong, PM2, PM5:Supporting -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Dec 22, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Centre for Genomic and Experimental Medicine, University of Edinburgh
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.34
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.81
D
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
4.4
H
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-7.7
D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.95
Loss of methylation at R132 (P = 0.0369);
MVP
0.95
MPC
0.41
ClinPred
1.0
D
GERP RS
2.2
Varity_R
0.95
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908173; hg19: chr20-45354069; COSMIC: COSV63716097; API