NM_005359.6(SMAD4):c.1498A>C (p.Ile500Leu) AND Juvenile polyposis syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 17, 2023
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:: RCV003763558.1

Allele description [Variation Report for NM_005359.6(SMAD4):c.1498A>C (p.Ile500Leu)]

NM_005359.6(SMAD4):c.1498A>C (p.Ile500Leu)

Gene:

SMAD4:SMAD family member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q21.2

Genomic location:

Preferred name:

NM_005359.6(SMAD4):c.1498A>C (p.Ile500Leu)

HGVS:

NC_000018.10:g.51078306A>C
NG_013013.2:g.115267A>C
NM_001407041.1:c.1498A>C
NM_001407042.1:c.1498A>C
NM_005359.6:c.1498A>CMANE SELECT
NP_001393970.1:p.Ile500Leu
NP_001393971.1:p.Ile500Leu
NP_005350.1:p.Ile500Leu
NP_005350.1:p.Ile500Leu
LRG_318t1:c.1498A>C
LRG_318:g.115267A>C
LRG_318p1:p.Ile500Leu
NC_000018.9:g.48604676A>C
NM_005359.5:c.1498A>C
NR_176265.1:n.2149A>C

Protein change:

I500L

Molecular consequence:

NM_001407041.1:c.1498A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407042.1:c.1498A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005359.6:c.1498A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_176265.1:n.2149A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Juvenile polyposis syndrome (JPS)
Synonyms:: Polyposis juvenile intestinal; Polyposis familial of entire gastrointestinal tract
Identifiers:: MONDO: MONDO:0017380; MedGen: C0345893; Orphanet: 2929; OMIM: 174900

Recent activity

Clear Turn Off Turn On

Homo sapiens cDNA clone IMAGE:5450590, with apparent retained intron
Homo sapiens cDNA clone IMAGE:5450590, with apparent retained intron
gi|23025766|gb|BC034941.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004507800	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 17, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22158539, 22243968, 22585601, 24398790, 26636501, 27302097, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004507800

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 17, 2023)

germline

clinical testing

PubMed (7)
[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

Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.

Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, Destrée A, di Rocco M, Héron D, Jacquemont S, Marlin S, Simon M, Tolmie J, Verloes A, Casanova JL, Munnich A, Cormier-Daire V.

Nat Genet. 2011 Dec 11;44(1):85-8. doi: 10.1038/ng.1016.

PubMed [citation]

PMID:: 22158539

A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.

Caputo V, Cianetti L, Niceta M, Carta C, Ciolfi A, Bocchinfuso G, Carrani E, Dentici ML, Biamino E, Belligni E, Garavelli L, Boccone L, Melis D, Andria G, Gelb BD, Stella L, Silengo M, Dallapiccola B, Tartaglia M.

Am J Hum Genet. 2012 Jan 13;90(1):161-9. doi: 10.1016/j.ajhg.2011.12.011.

PubMed [citation]

PMID:: 22243968
PMCID:: PMC3257749

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV004507800.1

#	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 replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 500 of the SMAD4 protein (p.Ile500Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. This variant disrupts the p.Ile500 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22158539, 22243968, 22585601, 24398790, 26636501, 27302097). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 28, 2024

ClinVar

Relating variation to medicine