NM_030777.4:c.1334delG

Variant names:

• chr20-46726907-AG-A
• rs587776600
• NM_030777.4:c.1334delG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_030777.4(SLC2A10):​c.1334delG​(p.Gly445GlufsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SLC2A10 NM_030777.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.48

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]

ACMG classification

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 20-46726907-AG-A is Pathogenic according to our data. Variant chr20-46726907-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 4587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46726907-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A10	NM_030777.4	c.1334delG	p.Gly445GlufsTer40	frameshift_variant	Exon 3 of 5	ENST00000359271.4	NP_110404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A10	ENST00000359271.4	c.1334delG	p.Gly445GlufsTer40	frameshift_variant	Exon 3 of 5	1	NM_030777.4	ENSP00000352216.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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: 0.000191

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251486 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135920

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

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: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 259 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 125 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

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: 0.000219

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74344

Gnomad4 AFR AF: 0.0000965

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: 0.000191

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arterial tortuosity syndrome Pathogenic:8 Other:1

May 24, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 29, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly445GlufsX40 variant in SLC2A10 has been reported in the homozygous or compound heterozygous state in at least 8 individuals with arterial tortuosity syndrome (1 homozygote, 7 compound heterozygotes, the majority of whom had a second disease causing variant in SLC210A; Coucke 2006 PMID: 16550171, Callewaert 2008 PMID: 17935213, Ritelli 2009 PMID: 19781076, Hardin 2018 PMID: 28726533). This variant segregated with disease in 7 affected relatives from 3 families (Coucke 2006 PMID: 16550171, Callewaert 2008 PMID: 17935213). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 4587) and has been identified 0.019% (13/68030) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2), which is consistent with a recessive carrier frequency. In vitro functional studies using of patient cells demonstrate a lack of protein in homozygous patients and about half of wild type expression in heterozygotes (Coucke 2006 PMID: 16550171), suggesting that this variant affects protein function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 445 and leads to a premature termination codon 40 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the SLC2A10 gene is an established disease mechanism in autosomal recessive arterial tortuosity syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive arterial tortuosity syndrome. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PS3_Supporting. -

Nov 16, 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.1334delG (p.Gly445GlufsX40) 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. The variant allele was found at a frequency of 8.4e-05 in 251486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC2A10 causing Arterial Tortuosity Syndrome (8.4e-05 vs 0.0016), allowing no conclusion about variant significance. c.1334delG has been reported in the literature in multiple homozygous individuals affected with Arterial Tortuosity Syndrome (e.g. Coucke_2006, Piccinelli_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Coucke_2006). The most pronounced variant effect results in severely reduced mRNA and protein expression in homozygous patient cells compared to unaffected controls. The following publications have been ascertained in the context of this evaluation (PMID: 16550171, 34847858). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 08, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC2A10 c.1334delG; p.Gly445GlufsTer40 variant (rs587776600) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with arterial tortuosity syndrome, and segregates with disease in at least one family (Callewaert 2008, Coucke 2006, Hardin 2018, Ritelli 2009). This variant is reported in ClinVar (Variation ID: 4587), and is found in the non-Finnish European population with an allele frequency of 0.015% (20/129188 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional analyses of patient cells demonstrate a lack of protein in homozygous patients and about half of wild type expression in heterozygotes (Coucke 2006). Based on available information, this variant is considered to be pathogenic. References: Callewaert BL et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008 Jan;29(1):150-8. Coucke PJ et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006 Apr;38(4):452-7. Hardin JS et al. Ophthalmic findings in patients with arterial tortuosity syndrome and carriers: A case series. Ophthalmic Genet. 2018 Jan-Feb;39(1):29-34. Ritelli M et al. Arterial tortuosity syndrome in two Italian paediatric patients. Orphanet J Rare Dis. 2009 Sep 25;4:20. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly445Glufs*40) 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). This variant is present in population databases (rs758681965, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with arterial tortuosity syndrome (PMID: 16550171, 17935213, 19781076, 28726533). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4587). For these reasons, this variant has been classified as Pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Nov 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1334delG pathogenic mutation, located in coding exon 3 of the SLC2A10 gene, results from a deletion of one nucleotide at nucleotide position 1334, causing a translational frameshift with a predicted alternate stop codon (p.G445Efs*40). This variant has been identified in the homozygous state and/or in conjunction with other SLC2A10 variant(s) in individual(s) with features consistent with arterial tortuosity syndrome (ATS) (Coucke PJ et al. Nat Genet. 2006;38(4):452-7; Callewaert BL et al. Hum Mutat. 2008;29(1):150-8). 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

Feb 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect in SLC2A10-encoded protein levels in individuals homozygous for the variant that showed nearly absent expression, while heterozygous carriers in the family expressed about half the amount of protein compared to wild-type and deficiencies in protein transport (Coucke et al., 2006; Nemeth et al., 2016); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 4587; ClinVar); This variant is associated with the following publications: (PMID: 27153185, 16550171, 17935213, 17163528, 19781076, 31589614, 28726533, 31786173) -

SLC2A10-related disorder Pathogenic:1

Aug 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC2A10 c.1334delG variant is predicted to result in a frameshift and premature protein termination (p.Gly445Glufs*40). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with arterial tortuosity syndrome (Coucke et al. 2006. PubMed ID: 16550171; Callewaert et al. 2008. PubMed ID: 17935213; Hardin et al. 2018. PubMed ID: 28726533). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-45355546-AG-A). Frameshift variants in SLC2A10 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587776600; hg19: chr20-45355546;