NM_030777.4(SLC2A10):c.1334del (p.Gly445fs) AND Arterial tortuosity syndrome

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004849.31

Allele description [Variation Report for NM_030777.4(SLC2A10):c.1334del (p.Gly445fs)]

NM_030777.4(SLC2A10):c.1334del (p.Gly445fs)

Gene:

SLC2A10:solute carrier family 2 member 10 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_030777.4(SLC2A10):c.1334del (p.Gly445fs)

HGVS:

NC_000020.10:g.45355548delG
NC_000020.11:g.46726909del
NG_016284.1:g.22270del
NM_030777.4:c.1334delMANE SELECT
NP_110404.1:p.Gly445fs
NC_000020.10:g.45355547del
NC_000020.10:g.45355548del
NC_000020.10:g.45355548delG
NC_000020.11:g.46726909delG
NM_030777.3:c.1334delG
NM_030777.4:c.1334delGMANE SELECT
NP_110404.1:p.Gly445fsTer40
p.G445EfsX40

Protein change:

G445fs

Links:

OMIM: 606145.0003; dbSNP: rs587776600

NCBI 1000 Genomes Browser:

rs587776600

Molecular consequence:

NM_030777.4:c.1334del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Arterial tortuosity syndrome (ATORS)
Identifiers:: MONDO: MONDO:0008818; MedGen: C1859726; Orphanet: 3342; OMIM: 208050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025025	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2008)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 14569121, 16550171, 17935213
SCV000195651	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 16550171, 17935213, 19781076
SCV000692260	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Pathogenic (May 24, 2017)	germline	clinical testing
SCV001413726	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 16, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22488877, 23494979, 16550171, 17935213, 19781076, 28726533, 28492532
SCV002020700	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002048382	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Sep 1, 2021)	germline	clinical testing	Citation Link,
SCV004222787	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16550171, 34847858 Citation Link,
SCV004847427	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19781076, 16550171, 17935213, 28726533, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Homozygosity mapping of a gene for arterial tortuosity syndrome to chromosome 20q13.

Coucke PJ, Wessels MW, Van Acker P, Gardella R, Barlati S, Willems PJ, Colombi M, De Paepe A.

J Med Genet. 2003 Oct;40(10):747-51.

PubMed [citation]

PMID:: 14569121
PMCID:: PMC1735278

Adult presentation of arterial tortuosity syndrome in a 51-year-old woman with a novel homozygous c.1411+1G>A mutation in the SLC2A10 gene.

Castori M, Ritelli M, Zoppi N, Molisso L, Chiarelli N, Zaccagna F, Grammatico P, Colombi M.

Am J Med Genet A. 2012 May;158A(5):1164-9. doi: 10.1002/ajmg.a.35266. Epub 2012 Apr 9.

PubMed [citation]

PMID:: 22488877

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000025025.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a consanguineous Italian kindred with arterial tortuosity syndrome (ATORS; 208050), the Sicilian family studied by Coucke et al. (2003) with 4 affected children in 2 sibships, Coucke et al. (2006) identified a homozygous frameshift mutation in the SLC2A10 gene, 1334delG (Gly445fsTer484), in affected individuals.

Callewaert et al. (2008) identified the 1334delG mutation in affected members of 4 European families with arterial tortuosity syndrome. Haplotype analysis suggested a founder effect. The authors noted that the mutation occurs in a highly conserved region in exon 3 and disrupts the endofacial loop between TMD10 and TMD11. In all patients, the mutation was in compound heterozygosity with another pathogenic SLC2A10 mutation (see, e.g., 606145.0005 and 606145.0006).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000195651.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000692260.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001413726.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020700.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048382.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004222787.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847427.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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