NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val) AND not provided

Germline classification:: Pathogenic (12 submissions)
Last evaluated:: Apr 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000059733.35

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000091303	UniProtKB/Swiss-Prot	no classification provided	not provided	not provided	not provided	PubMed (2) [See all records that cite these PMIDs] 22243968, 22158539
SCV000211666	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 1, 2022)	germline	clinical testing	Citation Link,
SCV000692039	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV000706695	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Mar 16, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22158539, 22243968, 22585601, 24398790, 26636501 Citation Link,
SCV000778276	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	no assertion criteria provided	Pathogenic (Jul 31, 2017)	germline	clinical testing
SCV001808895	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001926924	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001953780	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV003802792	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020)	Pathogenic (Nov 26, 2022)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22158539, 36194927, 22243968, 27302097 Citation Link,
SCV004026072	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005042338	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2024)	germline	clinical testing	Citation Link,
SCV005198290	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2024)	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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations of SMAD4 account for both LAPS and Myhre syndromes.

Lindor NM, Gunawardena SR, Thibodeau SN.

Am J Med Genet A. 2012 Jun;158A(6):1520-1. doi: 10.1002/ajmg.a.35374. Epub 2012 May 14. No abstract available.

PubMed [citation]

PMID:: 22585601

SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

Piccolo P, Mithbaokar P, Sabatino V, Tolmie J, Melis D, Schiaffino MC, Filocamo M, Andria G, Brunetti-Pierri N.

Eur J Hum Genet. 2014 Aug;22(8):988-94. doi: 10.1038/ejhg.2013.283. Epub 2014 Jan 8.

PubMed [citation]

PMID:: 24398790
PMCID:: PMC3984901

See all PubMed Citations (8)

Details of each submission

From UniProtKB/Swiss-Prot, SCV000091303.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (2)

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

From GeneDx, SCV000211666.13

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

Description

Published functional studies demonstrate a damaging effect as p.(I500V) resulted in dysregulation of both matrix metalloproteinases and related inhibitors (Piccolo et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633542, 34620752, 34556655, 34849273, 22243968, 22585601, 22158539, 27302097, 26636501, 27562837, 25533962, 25363768, 28991257, 28191890, 30921096, 29230941, 28562390, 28867141, 31654632, 32021609, 32175297, 31618753, 31447099, 28714951, 32371413, 32368696, 34015905, 30787465, 31785789, 17873119, 18823382, 15235019, 24398790)

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV000692039.1

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

#	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

From Eurofins Ntd Llc (ga), SCV000706695.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

#	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		2	not provided	not provided	not provided

From Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes, SCV000778276.1

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

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

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808895.1

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

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001926924.1

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

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001953780.1

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

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

From Illumina Laboratory Services, Illumina, SCV003802792.1

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

Description

The SMAD4 c.1498A>G (p.Ile500Val) missense variant results in the substitution of isoleucine at amino acid position 500 with valine. This variant is the most commonly reported variant in Myhre syndrome and has been described in at least 34 affected individuals, in many of whom it occurred de novo (PMID: 27302097; PMID: 36194927). The c.1498A>G variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000009 in the European (non-Finnish) population (version 2.1.1). Two other missense changes affecting the same position, p.Ile500Thr and p.Ile500Met, have also been reported in individuals with Myhre syndrome (PMID: 27302097). The valine and threonine changes have been shown to disrupt TGF-β and BMP signaling in HEK293T cells and patient fibroblasts, and the p.Ile500Val variant has been specifically shown to have a dominant-negative effect on wild-type SMAD4 (PMID: 22158539; PMID 36194927). Based on the available evidence, the c.1498A>G (p.Ile500Val) variant is classified as pathogenic for Myhre syndrome.

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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV004026072.1

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

Description

PM1, PS3, PP3, PM5, PM2_SUP

#	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 CeGaT Center for Human Genetics Tuebingen, SCV005042338.6

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

Description

SMAD4: PS2:Very Strong, PM1, PM2, PM5, PP2, PP3, PS3:Supporting, PS4:Supporting

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198290.1

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

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

Last Updated: Nov 24, 2024

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