ClinVar Genomic variation as it relates to human health

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant reported in 1 Marfan proband

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Identified in a Chinese individual with a Marfanoid habitus and in a Chinese individual with sporadic aortic dissection, but familial segregation data and additional clinical information were not included (Chung et al., 2009; Li et al., 2018); Identified in an individual with isolated sagittal single suture craniosynostosis, but familial segregation data and further clinical information were not provided (Clarke et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30341550, 19533785, 29168297)

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 190 of the TGFBR2 protein (p.Arg190His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 19533785, 29168297, 30341550). ClinVar contains an entry for this variant (Variation ID: 403531). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces arginine with histidine at codon 190 of the TGFBR2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 19533785) and an individual with sporadic case of aortic dissection (PMID: 30341550). This variant was also reported in one individual with sagittal single suture craniosynostosis (PMID: 29168297). This variant has been identified in 14/282608 chromosomes 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.

The TGFBR2 c.569G>A; p.Arg190His variant (rs780542125), is reported in the literature in an individual in a cohort of Marfan syndrome patients (Chung 2009), an individual with aortic dissection (Li 2018) and an individual with single suture craniosynostosis (Clarke 2018). This variant is reported in ClinVar (Variation ID: 403531). This variant is also found in the general population with an overall allele frequency of 0.005% (14/282608 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.696). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Chung BH et al. Identification of novel FBN1 and TGFBR2 mutations in 65 probands with Marfan syndrome or Marfan-like phenotypes. Am J Med Genet A. 2009 Jul;149A(7):1452-9. PMID: 19533785. Clarke CM et al. Single suture craniosynostosis: Identification of rare variants in genes associated with syndromic forms. Am J Med Genet A. 2018 Feb;176(2):290-300. PMID: 29168297. Li Z et al. A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection. Sci China Life Sci. 2018 Dec;61(12):1545-1553. PMID: 30341550.

This missense variant replaces arginine with histidine at codon 190 of the TGFBR2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 19533785) and an individual with sporadic case of aortic dissection (PMID: 30341550). This variant was also reported in one individual with sagittal single suture craniosynostosis (PMID: 29168297). This variant has been identified in 14/282608 chromosomes 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.

The p.R190H variant (also known as c.569G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in an individual with skeletal involvement who did not meet Ghent criteria (Chung BH et al. Am J Med Genet A, 2009 Jul;149A:1452-9), and has also been detected in an individual with craniosynostosis and an individual with aortic dissection; however, additional clinical details were limited (Clarke CM et al. Am J Med Genet A, 2018 02;176:290-300; Li Z et al. Sci China Life Sci, 2018 12;61:1545-1553). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.