NM_003183.6(ADAM17):c.2174G>A (p.Arg725His) AND Inflammatory skin and bowel disease, neonatal, 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 4, 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:: RCV001217588.6

Allele description [Variation Report for NM_003183.6(ADAM17):c.2174G>A (p.Arg725His)]

NM_003183.6(ADAM17):c.2174G>A (p.Arg725His)

Genes:

ADAM17:ADAM metallopeptidase domain 17 [Gene - OMIM - HGNC]
IAH1:isoamyl acetate hydrolyzing esterase 1 (putative) [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p25.1

Genomic location:

Preferred name:

NM_003183.6(ADAM17):c.2174G>A (p.Arg725His)

HGVS:

NC_000002.12:g.9490478C>T
NG_029873.1:g.70311G>A
NM_001382777.1:c.1514G>A
NM_001382778.1:c.1277G>A
NM_003183.6:c.2174G>AMANE SELECT
NP_001369706.1:p.Arg505His
NP_001369707.1:p.Arg426His
NP_003174.3:p.Arg725His
LRG_1203t1:c.2174G>A
LRG_1203:g.70311G>A
LRG_1203p1:p.Arg725His
NC_000002.11:g.9630607C>T
NM_003183.5:c.2174G>A

Protein change:

R426H

Links:

dbSNP: rs147275585

NCBI 1000 Genomes Browser:

rs147275585

Molecular consequence:

NM_001382777.1:c.1514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001382778.1:c.1277G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003183.6:c.2174G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inflammatory skin and bowel disease, neonatal, 1
Identifiers:: MONDO: MONDO:0013693; MedGen: C3280501; Orphanet: 294023; OMIM: 614328

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001389434	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 4, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31060243, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001389434

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 4, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Functional Characterization of Colon Cancer-Associated Mutations in ADAM17: Modifications in the Pro-Domain Interfere with Trafficking and Maturation.

Pavlenko E, Cabron AS, Arnold P, Dobert JP, Rose-John S, Zunke F.

Int J Mol Sci. 2019 May 4;20(9). doi:pii: E2198. 10.3390/ijms20092198. Review.

PubMed [citation]

PMID:: 31060243
PMCID:: PMC6539446

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 Invitae, SCV001389434.4

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 725 of the ADAM17 protein (p.Arg725His). This variant is present in population databases (rs147275585, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ADAM17-related conditions. ClinVar contains an entry for this variant (Variation ID: 946680). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ADAM17 function (PMID: 31060243). 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: Feb 7, 2023

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