NM_005359.6(SMAD4):c.1486C>T (p.Arg496Cys) AND Juvenile polyposis syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 26, 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:: RCV002228175.11

Allele description [Variation Report for NM_005359.6(SMAD4):c.1486C>T (p.Arg496Cys)]

NM_005359.6(SMAD4):c.1486C>T (p.Arg496Cys)

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.1486C>T (p.Arg496Cys)

Other names:

p.R496C:CGT>TGT

HGVS:

NC_000018.10:g.51078294C>T
NG_013013.2:g.115255C>T
NM_005359.6:c.1486C>TMANE SELECT
NP_005350.1:p.Arg496Cys
NP_005350.1:p.Arg496Cys
LRG_318t1:c.1486C>T
LRG_318:g.115255C>T
LRG_318p1:p.Arg496Cys
NC_000018.9:g.48604664C>T
NM_005359.5:c.1486C>T

Protein change:

R496C

Links:

dbSNP: rs397518413

NCBI 1000 Genomes Browser:

rs397518413

Molecular consequence:

NM_005359.6:c.1486C>T - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000632767	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24424121, 24715504, 24398790, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000632767

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 26, 2023)

germline

clinical testing

PubMed (4)
[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

Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

Michot C, Le Goff C, Mahaut C, Afenjar A, Brooks AS, Campeau PM, Destree A, Di Rocco M, Donnai D, Hennekam R, Heron D, Jacquemont S, Kannu P, Lin AE, Manouvrier-Hanu S, Mansour S, Marlin S, McGowan R, Murphy H, Raas-Rothschild A, Rio M, Simon M, et al.

Eur J Hum Genet. 2014 Nov;22(11):1272-7. doi: 10.1038/ejhg.2013.288. Epub 2014 Jan 15. Erratum in: Eur J Hum Genet. 2014 Nov;22(11):1340.

PubMed [citation]

PMID:: 24424121
PMCID:: PMC4200423

Novel SMAD4 mutation causing Myhre syndrome.

Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M.

Am J Med Genet A. 2014 Jul;164A(7):1835-40. doi: 10.1002/ajmg.a.36544. Epub 2014 Apr 8.

PubMed [citation]

PMID:: 24715504

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000632767.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 496 of the SMAD4 protein (p.Arg496Cys). This variant is present in population databases (rs397518413, gnomAD 0.01%). This missense change has been observed in individual(s) with Myhre syndrome (PMID: 24424121, 24715504). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 88673). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SMAD4 function (PMID: 24398790). For these reasons, this variant has been classified as Pathogenic.

#	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: May 7, 2024

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