chr15-67181297-G-A

Variant names:

• chr15-67181297-G-A
• rs387906853
• NM_005902.4:c.715G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_005902.4(SMAD3):​c.715G>A​(p.Glu239Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.87

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain MH2 (size 193) in uniprot entity SMAD3_HUMAN there are 36 pathogenic changes around while only 0 benign (100%) in NM_005902.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMAD3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 3.4782 (above the threshold of 3.09). Trascript score misZ: 4.3526 (above the threshold of 3.09). GenCC associations: The gene is linked to familial thoracic aortic aneurysm and aortic dissection, aneurysm-osteoarthritis syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 15-67181297-G-A is Pathogenic according to our data. Variant chr15-67181297-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67181297-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.715G>A	p.Glu239Lys	missense_variant	Exon 6 of 9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.715G>A	p.Glu239Lys	missense_variant	Exon 6 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Jan 27, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E239K variant (also known as c.715G>A), located in coding exon 6 of the SMAD3 gene, results from a G to A substitution at nucleotide position 715. The glutamic acid at codon 239 is replaced by lysine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with Loeys-Dietz syndrome (Regalado ES et al. Circ Res, 2011 Sep;109:680-6; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Panesi P et al. Ann Thorac Surg, 2015 Jan;99:303-5; Arnaud P et al. Genet Med, 2019 Sep;21:2015-2024). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 239 of the SMAD3 protein (p.Glu239Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 21778426, 25555948, 30739908, 35487415; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30311). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SMAD3 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:2

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMAD3: PM2, PP1, PP2, PP3, PP4 -

Aug 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple unrelated patients from different ethnic backgrounds with TAAD referred for genetic testing at GeneDx and in the published literature (PMID: 29392890, 25644172, 21778426, 25555948, 30739908, 30661052); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25555948, 25644172, 21778426, 28185953, 30661052, 30739908, 35487415, 31447099, 29392890) -

Aneurysm-osteoarthritis syndrome Pathogenic:2

Jul 06, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.715G>A (p.Glu239Lys) variant in the SMAD3 gene has been reported in multiple patients with thoracic aortic disorders [PMID 21778426, 25644172, 25555948]. Among them, this variant was detected in three affected siblings, all carriers, while another sibling was unaffected and non carrier [PMID 21778426]. This variant is conserved in mammals. While not clinically validated, computer-based algorithms SIFT and Polyphen-2 predict the protein change to be deleterious. It is thus classified as likely pathogenic. -

Sep 02, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		1.0
MutPred		0.91		Gain of methylation at E239 (P = 0.0202);.;.;.;.;.;.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906853; hg19: chr15-67473635; COSMIC: COSV59283256; COSMIC: COSV59283256;