NM_030777.4(SLC2A10):c.515C>T (p.Thr172Ile) AND Arterial tortuosity syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 29, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000319871.28

Allele description [Variation Report for NM_030777.4(SLC2A10):c.515C>T (p.Thr172Ile)]

NM_030777.4(SLC2A10):c.515C>T (p.Thr172Ile)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_030777.4(SLC2A10):c.515C>T (p.Thr172Ile)

Other names:

p.T172I:ACT>ATT

HGVS:

NC_000020.11:g.46725551C>T
NG_016284.1:g.20912C>T
NM_030777.4:c.515C>TMANE SELECT
NP_110404.1:p.Thr172Ile
NC_000020.10:g.45354190C>T
NM_030777.3:c.515C>T

Protein change:

T172I

Links:

dbSNP: rs143301610

NCBI 1000 Genomes Browser:

rs143301610

Molecular consequence:

NM_030777.4:c.515C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000434153	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV000549181	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000884524	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Apr 6, 2022)	germline	clinical testing	Citation Link,
SCV003920483	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Oct 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000434153.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Invitae, SCV000549181.10

#	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, SCV000884524.3

#	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.515C>T; p.Thr172Ile variant (rs143301610) is reported in the literature in an individual affected with aortopathy/aortic dilation (Wooderchak-Donahue 2015), but its clinical significance was not determined. This variant is also reported in ClinVar (Variation ID: 195383) and is found in the non-Finnish European population with an allele frequency of 0.135% (174/129040 alleles) in the Genome Aggregation Database. The threonine at codon 172 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.148). Due to limited information, the clinical significance of the p.Thr172Ile variant is uncertain at this time. References: Wooderchak-Donahue W et al., Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A. 2015 Aug;167A(8):1747-57. PMID: 25944730.

#	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 Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920483.1

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

Description

This variant has been reported in the literature in one individual with aortic dilation/dissection (Wooderchak-Donahue 2015 PMID:25944730). However, this variant is also present in 0.1% (174/129040) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-45354190-C-T) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:195383). This variant amino acid Isoleucine (Ile) is present in >15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.

#	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: Apr 15, 2024

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