ClinVar Genomic variation as it relates to human health

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.

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.

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.

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)

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.

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.

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 mutation was reported in association with arterial tortuosity syndrome (ATS) in the homozygous state in an Italian family with consanguinity (Coucke PJ et al. Nat Genet. 2006;38(4):452-7). This recurrent mutation, which is in the endofacial loop between TMD10 and TMD11, was also reported in four European families each in compound heterozygosity with another mutation (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.