NM_005359.6(SMAD4):c.220A>G (p.Ile74Val) AND Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 7, 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:: RCV004007407.2

Allele description [Variation Report for NM_005359.6(SMAD4):c.220A>G (p.Ile74Val)]

NM_005359.6(SMAD4):c.220A>G (p.Ile74Val)

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.220A>G (p.Ile74Val)

HGVS:

NC_000018.10:g.51047266A>G
NG_013013.2:g.84227A>G
NM_001407041.1:c.220A>G
NM_001407042.1:c.220A>G
NM_001407043.1:c.220A>G
NM_005359.6:c.220A>GMANE SELECT
NP_001393970.1:p.Ile74Val
NP_001393971.1:p.Ile74Val
NP_001393972.1:p.Ile74Val
NP_005350.1:p.Ile74Val
NP_005350.1:p.Ile74Val
LRG_318t1:c.220A>G
LRG_318:g.84227A>G
LRG_318p1:p.Ile74Val
NC_000018.9:g.48573636A>G
NM_005359.5:c.220A>G
NR_176264.1:n.758A>G
NR_176265.1:n.758A>G

Protein change:

I74V

Molecular consequence:

NM_001407041.1:c.220A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407042.1:c.220A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407043.1:c.220A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005359.6:c.220A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV004824168	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Mar 7, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004824168

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Mar 7, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004824168.1

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

Description

This missense variant replaces isoleucine with valine at codon 74 of the SMAD4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has been identified in 1/251074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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