ClinVar Genomic variation as it relates to human health

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.​

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

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.

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)

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.

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.

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, Ratajska_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29510914, 29392890, 36495030). ClinVar contains an entry for this variant (Variation ID: 263428). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.