VCV000136077.21 - ClinVar

NM_005359.6(SMAD4):c.671A>T (p.Gln224Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(10); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005359.6(SMAD4):c.671A>T (p.Gln224Leu)

Variation ID: 136077 Accession: VCV000136077.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q21.2 18: 51058128 (GRCh38) [ NCBI UCSC ] 18: 48584498 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 16, 2017	Sep 29, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005359.6:c.671A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005350.1:p.Gln224Leu	missense
NC_000018.10:g.51058128A>T
NC_000018.9:g.48584498A>T
NG_013013.2:g.95089A>T
LRG_318:g.95089A>T
LRG_318t1:c.671A>T	LRG_318p1:p.Gln224Leu

... more HGVS ... less HGVS

Protein change

Q224L

Other names

Canonical SPDI

NC_000018.10:51058127:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA332851 dbSNP: rs587780793 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SMAD4		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2160	2202

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Generalized juvenile polyposis/juvenile polyposis coli	Uncertain significance (1)	criteria provided, single submitter	Oct 27, 2017	RCV000123264.12
Juvenile polyposis syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 30, 2024	RCV001358798.12
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 27, 2023	RCV000986028.11
Familial thoracic aortic aneurysm and aortic dissection Hereditary cancer-predisposing syndrome	Likely benign (1)	criteria provided, single submitter	Aug 29, 2022	RCV002310680.9
Carcinoma of pancreas Juvenile polyposis syndrome Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Myhre syndrome	Uncertain significance (1)	criteria provided, single submitter	Sep 23, 2021	RCV002483236.8
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 23, 2023	RCV003315822.11
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	May 30, 2023	RCV003584556.1
SMAD4-related disorder	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2023	RCV003422007.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 27, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Juvenile polyposis syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785675.2 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Uncertain significance (Sep 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myhre syndrome Juvenile polyposis syndrome Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Familial pancreatic carcinoma Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002791178.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Apr 10, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004017807.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Mar 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SMAD4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004117235.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The SMAD4 c.671A>T variant is predicted to result in the amino acid substitution p.Gln224Leu. To our knowledge, this variant has not been reported in the … (more) The SMAD4 c.671A>T variant is predicted to result in the amino acid substitution p.Gln224Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-48584498-A-T) and has been interpreted as likely benign and variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/136077/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Oct 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202576.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Nov 04, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001134828.3 First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024	Comment: To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, … (more) To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000087 (3/34586 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (May 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004362344.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This missense variant replaces glutamine with leucine at codon 224 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces glutamine with leucine at codon 224 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 3/251320 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. (less)
Uncertain significance (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Juvenile polyposis syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166571.9 First in ClinVar: Jun 16, 2014 Last updated: Feb 20, 2024	Comment: This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 224 of the SMAD4 protein (p.Gln224Leu). … (more) This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 224 of the SMAD4 protein (p.Gln224Leu). This variant is present in population databases (rs587780793, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 136077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Oct 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004828048.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces glutamine with leucine at codon 224 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces glutamine with leucine at codon 224 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 3/251320 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. (less) Number of individuals with the variant: 2
Likely benign (Aug 29, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Familial thoracic aortic aneurysm and aortic dissection Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000277933.7 First in ClinVar: May 29, 2016 Last updated: Jun 09, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Oct 27, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325737.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with a personal history of breast cancer, melanoma, and segmental hyperpigmentation (PMID: 36809100); This variant is associated with the following publications: (PMID: 36809100) (less)
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Comment:

The SMAD4 c.671A>T variant is predicted to result in the amino acid substitution p.Gln224Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-48584498-A-T) and has been interpreted as likely benign and variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/136077/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000087 (3/34586 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This missense variant replaces glutamine with leucine at codon 224 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 3/251320 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.

Comment:

This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 224 of the SMAD4 protein (p.Gln224Leu). This variant is present in population databases (rs587780793, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 136077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with a personal history of breast cancer, melanoma, and segmental hyperpigmentation (PMID: 36809100); This variant is associated with the following publications: (PMID: 36809100)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs587780793 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_005359.6(SMAD4):c.671A>T (p.Gln224Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587780793 ...