U.S. flag

An official website of the United States government

NM_005359.6(SMAD4):c.1495T>C (p.Cys499Arg) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 29, 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:
RCV002319001.9

Allele description [Variation Report for NM_005359.6(SMAD4):c.1495T>C (p.Cys499Arg)]

NM_005359.6(SMAD4):c.1495T>C (p.Cys499Arg)

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.1495T>C (p.Cys499Arg)
HGVS:
  • NC_000018.10:g.51078303T>C
  • NG_013013.2:g.115264T>C
  • NM_005359.6:c.1495T>CMANE SELECT
  • NP_005350.1:p.Cys499Arg
  • NP_005350.1:p.Cys499Arg
  • LRG_318t1:c.1495T>C
  • LRG_318:g.115264T>C
  • LRG_318p1:p.Cys499Arg
  • NC_000018.9:g.48604673T>C
  • NM_005359.5:c.1495T>C
Protein change:
C499R
Links:
dbSNP: rs1060500738
NCBI 1000 Genomes Browser:
rs1060500738
Molecular consequence:
  • NM_005359.6:c.1495T>C - 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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001172145Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(Aug 29, 2023)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV001172145.4

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

Description

The p.C499R variant (also known as c.1495T>C), located in coding exon 11 of the SMAD4 gene, results from a T to C substitution at nucleotide position 1495. The cysteine at codon 499 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been observed in individuals meeting diagnostic criteria for Juvenile Polyposis and/or Hereditary Hemorrhagic Telangiectasia (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Chacko BM et al. Mol. Cell, 2004 Sep;15:813-23). In addition, this alteration is predicted to be deleterious by in silico analysis. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Nov 10, 2024