NM_005359.6(SMAD4):c.1333C>T (p.Arg445Ter) AND Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 9, 2024
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:: RCV000023059.12

Allele description [Variation Report for NM_005359.6(SMAD4):c.1333C>T (p.Arg445Ter)]

NM_005359.6(SMAD4):c.1333C>T (p.Arg445Ter)

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.1333C>T (p.Arg445Ter)

HGVS:

NC_000018.10:g.51076662C>T
NG_013013.2:g.113623C>T
NM_005359.6:c.1333C>TMANE SELECT
NP_005350.1:p.Arg445Ter
NP_005350.1:p.Arg445Ter
LRG_318t1:c.1333C>T
LRG_318:g.113623C>T
LRG_318p1:p.Arg445Ter
NC_000018.9:g.48603032C>T
NM_005359.5:c.1333C>T
p.R445*

Protein change:

R445*; ARG445TER

Links:

OMIM: 600993.0014; dbSNP: rs377767360

NCBI 1000 Genomes Browser:

rs377767360

Molecular consequence:

NM_005359.6:c.1333C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JPHT)
Synonyms:: JP/HHT SYNDROME; JUVENILE POLYPOSIS WITH HEREDITARY HEMORRHAGIC TELANGIECTASIA; POLYPOSIS, GENERALIZED JUVENILE, WITH PULMONARY ARTERIOVENOUS MALFORMATION; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008278; MedGen: C1832942; Orphanet: 2929; OMIM: 175050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000044350	OMIM	no assertion criteria provided	Pathogenic (May 1, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004931948	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Feb 9, 2024)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000044350

OMIM

no assertion criteria provided

Pathogenic
(May 1, 2011)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004931948

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Feb 9, 2024)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction.

Andrabi S, Bekheirnia MR, Robbins-Furman P, Lewis RA, Prior TW, Potocki L.

Am J Med Genet A. 2011 May;155A(5):1165-9. doi: 10.1002/ajmg.a.33968. Epub 2011 Apr 4.

PubMed [citation]

PMID:: 21465659

Details of each submission

From OMIM, SCV000044350.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 3 affected members of a family with a clinical variant of JPHT (175050), Andrabi et al. (2011) identified a heterozygous mutation in exon 10 of the SMAD4 gene, resulting in an arg445-to-ter (R445X) substitution. The clinical features in this family were unusual in that affected members had mitral valve prolapse, mitral valve regurgitation, and aortic dilatation in addition to gastrointestinal hamartomatous polyps; telangiectases were not reported. Andrabi et al. (2011) noted the role of SMAD4 in the TGF-beta-1 signaling pathway, suggesting overlap with other connective tissue disorders such as Marfan syndrome (154700) and Loeys-Dietz syndrome (see, e.g., 609192). The findings indicated that haploinsufficiency of SMAD4 may cause an aortopathy and mitral valve dysfunction.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004931948.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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