rs1060500766

Variant names:

• chr15-67187473-G-A
• rs1060500766
• NM_005902.4:c.1118G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-67187473-G-A
• chr15-67187473-G-T

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.1118G>A​(p.Arg373His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.77

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, 0.983
• PP5: Variant 15-67187473-G-A is Pathogenic according to our data. Variant chr15-67187473-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1118G>A	p.Arg373His	missense_variant	Exon 8 of 9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1118G>A	p.Arg373His	missense_variant	Exon 8 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 373 of the SMAD3 protein (p.Arg373His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 25944730, 30661052; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 405561). 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%. Experimental studies have shown that this missense change affects SMAD3 function (PMID: 16828225). This variant disrupts the p.Arg373 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 30661052; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Nov 15, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R373H variant (also known as c.1118G>A), located in coding exon 8 of the SMAD3 gene, results from a G to A substitution at nucleotide position 1118. The arginine at codon 373 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported 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). Additionally, this alteration was detected in a cancer cell line and suggested to possibly impact TGF-β signaling in in vitro assays, although the physiological relevance is unknown (Ku JL et al. Cancer Lett., 2007 Mar;247:283-92). 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. -

Jan 14, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jun 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP2, PP3, PM1, PM2, PS3_supporting, PS4_moderate -

Dec 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMAD3 c.1118G>A; p.Arg373His variant (rs1060500766, ClinVar Variation ID: 405561) is reported in the literature in individuals affected with thoracic aortic aneurysms, dissections, or dilation (Arnaud 2019, Hostetler 2019, Wooderchak-Donahue 2015, Yang 2020). Based on samples tested at ARUP la-boratories this variant has co-segregated with disease through at least 7 meiosis. This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Compu-tational analyses predict that this variant is deleterious (REVEL: 0.97). In cultured cells, this variant exhib-its mildly reduced transcriptional activation activity and altered localization in response to TGF-beta treatment (Ku 2007), although it is not certain whether these properties are physiologically relevant. Based on available information, this variant is considered to be likely pathogenic. 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 compli-cations from the Montalcino Aortic Consortium. J Med Genet. 2019 Apr;56(4):252-260. PMID: 30661052. Ku JL et al. Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: a novel mutation in Smad3 associated with the inactivation of TGF-beta-induced transcriptional acti-vation. Cancer Lett. 2007 Mar 18;247(2):283-92. PMID: 16828225 Yang H et al. Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients. Orphanet J Rare Dis. 2020 Jan 8;15(1):6. PMID: 31915033. 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 -

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
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	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.91
MutPred		0.93		Loss of MoRF binding (P = 0.0303);.;.;.;
MVP		0.96
MPC		2.7
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.96

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: rs1060500766; hg19: chr15-67479811; COSMIC: COSV59284912; COSMIC: COSV59284912;