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NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 9, 2021
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:
RCV004558272.1

Allele description [Variation Report for NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val)]

NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val)

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>G (p.Ile500Val)
Other names:
p.I500V:ATA>GTA
HGVS:
  • NC_000018.10:g.51078306A>G
  • NG_013013.2:g.115267A>G
  • NM_005359.6:c.1498A>GMANE SELECT
  • NP_005350.1:p.Ile500Val
  • NP_005350.1:p.Ile500Val
  • LRG_318t1:c.1498A>G
  • LRG_318:g.115267A>G
  • LRG_318p1:p.Ile500Val
  • NC_000018.9:g.48604676A>G
  • NM_005359.3:c.1498A>G
  • NM_005359.5:c.1498A>G
  • Q13485:p.Ile500Val
Protein change:
I500V; ILE500VAL
Links:
UniProtKB: Q13485#VAR_067604; UniProtKB/Swiss-Prot: VAR_067604; OMIM: 600993.0016; dbSNP: rs281875322
NCBI 1000 Genomes Browser:
rs281875322
Molecular consequence:
  • NM_005359.6:c.1498A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:
Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:
MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086
Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000741420Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 9, 2021) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV000741420.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.1498A>G (p.I500V) alteration is located in exon 12 (coding exon 11) of the SMAD4 gene. This alteration results from an A to G substitution at nucleotide position 1498, causing the isoleucine (I) at amino acid position 500 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the SMAD4 c.1498A>G alteration was observed in <0.01% (1/251462) of total alleles studied. This alteration has been previously reported as de novo in multiple unrelated patients with Myhre syndrome and affects a known mutational hotspot (Le Goff, 2011; Caputo, 2012; Lin 2016; Alagia, 2018; Yu, 2019; Varenyiova, 2020). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.I500V alteration interferes with ubiquitination and degradation of SMAD4 resulting in accumulation of protein and induction of the TGFbeta pathway (Le Goff, 2011; Caputo, 2012; Piccolo, 2014). The in silico prediction for the p.I500V alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 24, 2024