rs886038803

chr15-67164957-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_005902.4(SMAD3):c.269G>A(p.Arg90His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R90C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:6
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 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 chr15-67164956-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426202.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.
• PP2: Missense variant where missense usually causes diseases, SMAD3
• PP5: Variant 15-67164957-G-A is Pathogenic according to our data. Variant chr15-67164957-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263428.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=6, Pathogenic=1}. Variant chr15-67164957-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.269G>A	p.Arg90His	missense_variant	2/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.269G>A	p.Arg90His	missense_variant	2/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461534 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

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.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aneurysm-osteoarthritis syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 16, 2023	This missense variant replaces arginine with histidine at codon 90 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 an individual suspected of having Loeys-Dietz syndrome (PMID: 29392890), and in another two individuals with clinical features of SMAD3-related diseases (PMID: 29510914, ClinVar RCV000246998.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg90Cys and p.Arg90dup, have also been reported in individuals affected with thoracic aortic aneurysm and dissection or related conditions (PMID: 25944730, 30661052, 32154675, ClinVar RCV000534111.8), indicating that arginine at this position is important for SMAD3 protein function. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3 (MIM#613795). Dominant negative is also a suggested mechanism of disease of missense variants (PMID: 30661052). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported for this gene (PMID: 32154675). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2 & v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. This alternative change (p.Arg90Cys) has been classified as a VUS and likely pathogenic, and has been observed in several individuals with aortic involvement or thoracic aortic aneurysm and dissection (ClinVar, Arno, G. et al. (2012), PMID: 25944730, PMID: 30661052). Additionally, an inframe duplication of this residue (p.Arg90dup) has also been described as pathogenic, and observed in a family with SMAD3-related disease (ClinVar, PMID: 32154675). (I) 0804 - This variant has previously been described as a variant of uncertain significance in multiple independent cases with consistent phenotype despite being absent in the general population (ClinVar). However, it has also been regarded likely pathogenic in ClinVar by one clinical laboratory. In addition, this variant has been reported in two unrelated families with Loeys-Dietz syndrome or aortic root dissection, and was classified as likely pathogenic or pathogenic (PMID: 29510914, PMID: 29392890). (SP) 0905 - No published segregation evidence has been identified for this variant. However, the variant has been noted to segregate within this proband's family (personal communication). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	SMAD3 NM_005902.3 exon 4 p.Arg90His (c.269G>A): This variant has been reported in the literature in one individual with suspected Loeys-Dietz syndrome (Schepers 2018 PMID:29392890). This variant is not present in large control databases but is present in ClinVar (Variation ID:263428). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 90 of the SMAD3 protein (p.Arg90His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SMAD3-related diseases and/or thoracic aortic aneurysms and dissections (PMID: 29392890, 29510914, 36495030). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 263428). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg90 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25944730, 30661052, 32154675; 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 21, 2021

Variant summary: SMAD3 c.269G>A (p.Arg90His) results in a non-conservative amino acid change located in the MAD homology 1, Dwarfin-type domain (IPR003619) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes (gnomAD). c.269G>A has been reported in the literature in individuals affected with cardiac disease (Schepers_2018, Hicks_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2023

Reported in association with SMAD3-related disorders in published literature (Hicks et al., 2018; Schepers et al., 2018; Ratajska et al., 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: 29510914, 36495030, 29392890) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2019

The p.R90H (also known as c.269G>A) variant is located in coding exon 2 of the SMAD3 gene. This variant results from an G to A substitution at nucleotide position 269. The arginine at codon 90 is replaced by histidine, an amino acid with some similar properties. This alteration has been reported in association with Loeys Dietz syndrome (Schepers D et al. Hum. Mutat., 2018 05;39:621-634). This variant was observed in 2 out of 3 unaffected children of a female proband tested by our laboratory. The proband's clinical findings include easy bruising and shiny translucent skin, multiple gastroduodenal bleeds, multiple aneurysms and aortic dissection. The proband's 3 unaffected children all had normal echocardiogram results. This amino acid position is highly conserved in available vertebrate species. This variant is predicted to be probably damaging by PolyPhen and deleterious by SIFT in silico analyses. Since supporting evidence for this variant is limited at this time, the clinical significance of this variant remains unclear.​ -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	34
Dann	Benign	0.96
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.64	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Uncertain	-4.0	D
Vest4		0.42
MVP		0.92
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886038803; hg19: chr15-67457295; COSMIC: COSV59287268; COSMIC: COSV59287268;