15-67187472-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_005902.4(SMAD3):c.1117C>T(p.Arg373Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,260 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373H) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 5.99

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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005902.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-67187473-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405561.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, SMAD3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 15-67187472-C-T is Pathogenic according to our data. Variant chr15-67187472-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213774.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.1117C>T	p.Arg373Cys	missense_variant	8/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.1117C>T	p.Arg373Cys	missense_variant	8/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the SMAD3 protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 30661052; Invitae; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 213774). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function. This variant disrupts the p.Arg373 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16828225, 25944730, 30661052; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2021	The p.R373C variant (also known as c.1117C>T), located in coding exon 8 of the SMAD3 gene, results from a C to T substitution at nucleotide position 1117. The arginine at codon 373 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a few individuals with thoracic aortic aneurysm (Arnaud P et al. Genet Med, 2019 09;21:2015-2024; Hostetler EM et al. J Med Genet, 2019 04;56:252-260). Another alteration at the same codon, p.R373H (c.1118G>A), has been detected in multiple individuals with thoracic aortic aneurysm, including one individual with additional concerns for a connective tissue disorder (Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57; Arnaud P et al. Genet Med, 2019 09;21:2015-2024; Hostetler EM et al. J Med Genet, 2019 04;56:252-260; Yang H et al. Orphanet J Rare Dis, 2020 01;15:6; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 07, 2023	This missense variant replaces arginine with cysteine at codon 373 in the MH2 protein interaction domain of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with thoracic aortic aneurysms and dissections (PMID: 30661052, 30739908) or related conditions (ClinVar SCV000658868.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg373His, is known to be pathogenic (Clinvar variation ID: 405561), indicating that arginine at this position is important for SMAD3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aneurysm-osteoarthritis syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	The SMAD3 c.1117C>T; p.Arg373Cys variant (rs863223746) is reported in the literature in individuals affected with thoracic aortic aneurysms, dissections, or dilation (Arnaud 2019, Hostetler 2019, Li 2021). This variant is reported in ClinVar (Variation ID: 213774) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.958). Additionally, another variant at this codon (c.1118G>A, p.Arg373His) has been reported in individuals with aortic dilation/dissection and is considered likely pathogenic (Hostetler 2019, Wooderchak-Donahue 2015). Due to limited information, the clinical significance of the p.Arg373Cys variant is uncertain at this time. References: Arnaud P et al. Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). Genet Med. 2019 Sep;21(9):2015-2024. PMID: 30739908. Hostetler EM et al. SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium. J Med Genet. 2019 Apr;56(4):252-260. PMID: 30661052. Li Y et al. Evaluating the monogenic contribution and genotype-phenotype correlation in patients with isolated thoracic aortic aneurysm. Eur J Hum Genet. 2021 Jul;29(7):1129-1138. PMID: 33824467. Wooderchak-Donahue W et al. Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A. 2015 Aug;167A(8):1747-57. PMID: 25944730. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 04, 2023	This missense variant replaces arginine with cysteine at codon 373 of the SMAD3 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysms and dissections (PMID: 30739908). This variant has not been identified 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. -

Isolated thoracic aortic aneurysm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2023

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: 30661052, 30739908, 33824467) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.88
MutPred		0.92		Loss of MoRF binding (P = 0.014);.;.;.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs863223746; hg19: chr15-67479810; COSMIC: COSV59282622; COSMIC: COSV59282622;