NM_014244.5(ADAMTS2):c.2866G>A (p.Ala956Thr) AND Ehlers-Danlos syndrome, dermatosparaxis type

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 27, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001277847.3

Allele description [Variation Report for NM_014244.5(ADAMTS2):c.2866G>A (p.Ala956Thr)]

NM_014244.5(ADAMTS2):c.2866G>A (p.Ala956Thr)

Gene:

ADAMTS2:ADAM metallopeptidase with thrombospondin type 1 motif 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q35.3

Genomic location:

Preferred name:

NM_014244.5(ADAMTS2):c.2866G>A (p.Ala956Thr)

Other names:

p.Ala956Thr

HGVS:

NC_000005.10:g.179125065C>T
NG_023212.3:g.225264G>A
NM_014244.5:c.2866G>AMANE SELECT
NP_055059.2:p.Ala956Thr
NC_000005.9:g.178552066C>T
NG_023212.2:g.225264G>A

Protein change:

A956T

Links:

dbSNP: rs375191740

NCBI 1000 Genomes Browser:

rs375191740

Molecular consequence:

NM_014244.5:c.2866G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Ehlers-Danlos syndrome, dermatosparaxis type
Synonyms:: EDS VIIC; Dermatosparaxis; Ehlers-Danlos syndrome type 7C (formerly); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009161; MedGen: C2700425; Orphanet: 1901; OMIM: 225410

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001464825	Natera, Inc.	no assertion criteria provided	Likely benign (May 27, 2020)	germline	clinical testing
SCV003255136	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001464825

Natera, Inc.

no assertion criteria provided

Likely benign
(May 27, 2020)

germline

clinical testing

SCV003255136

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 27, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Natera, Inc., SCV001464825.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003255136.1

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 956 of the ADAMTS2 protein (p.Ala956Thr). This variant is present in population databases (rs375191740, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 989941). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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