rs370547023

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_030777.4(SLC2A10):c.1330C>T(p.Arg444Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,006 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SLC2A10
NM_030777.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 1.99

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]

SLC2A10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-46726905-C-T is Pathogenic according to our data. Variant chr20-46726905-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A10	NM_030777.4 linkuse as main transcript	c.1330C>T	p.Arg444Ter	stop_gained	3/5	ENST00000359271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A10	ENST00000359271.4 linkuse as main transcript	c.1330C>T	p.Arg444Ter	stop_gained	3/5	1	NM_030777.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251470

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arterial tortuosity syndrome

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Feb 08, 2022	ACMG categories: PVS1,PP3,PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 161101). This premature translational stop signal has been observed in individual(s) with arterial tortuosity syndrome (PMID: 17163528). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs370547023, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg444*) in the SLC2A10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC2A10 are known to be pathogenic (PMID: 17935213, 22488877, 23494979). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2023	Variant summary: SLC2A10 c.1330C>T (p.Arg444X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At least one truncation downstream of this position have been reported in association with Arterial tortuosity syndrome in HGMD. The variant allele was found at a frequency of 4e-06 in 251470 control chromosomes. c.1330C>T has been reported in the literature in an individual affected with Arterial Tortuosity Syndrome (Drera_2007). Experimental evidence from fibroblasts from the patient reported in Drera, et al showed the genotype resulted in markedly reduced transport of DAA through endomembranes (Nemeth_2016) as well as absence of the typical patterns of GLUT10 perinuclear and mitochondrial decoration via immunostaining (Gamberucci_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2023

The p.R444* pathogenic mutation (also known as c.1330C>T), located in coding exon 3 of the SLC2A10 gene, results from a C to T substitution at nucleotide position 1330. This changes the amino acid from an arginine to a stop codon within coding exon 3. This variant was has been detected in the compound heterozygous state with a second SLC2A10 alteration in an individual with arterial tortuosity syndrome (Drera B et al. Am J Med Genet A, 2007 Jan;143A:216-8). Functional studies have indicated this variant impacts protein function (Zoppi N et al. Hum Mol Genet, 2015 Dec;24:6769-87; Németh CE et al. FEBS Lett, 2016 Jun;590:1630-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2017

The R444X variant in the SLC2A10 gene has been reported in an Italian patient who was compound heterozygous for theR444X nonsense variant and the E437K missense variant (Drera et al., 2007). Drera et al. (2007) describe a 14 year old child with clinical features of ATS including stenosis, and tortuosity of the left pulmonary artery, tortuosity of carotid, vertebral, and intracerebral arteries and a family history significant for two deceased siblings with findings suggestive of ATS. R444X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Nemeth et al. (2016) performed in vivo studies from fibroblasts of the patient described by Drera et al. (2007) demonstrating the absence of mRNA due to nuclear mediated decay, with restoration of normal endomembrane transport of DAA when transfected with wild-type SCL10A2. Other nonsense variants in the SLC2A10 gene have been reported in Human Gene Mutation Database in association with ATS (Stenson et al., 2014). Furthermore, the R444X variant is not observed at asignificant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). In summary, although R444X in the SLC2A10 gene is interpreted as a likely pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.86

MutationTaster

Benign

1.0

Vest4

0.92

GERP RS

2.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over