Submissions for variant NM_000660.7(TGFB1):c.653G>A (p.Arg218His)

dbSNP: rs104894720

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001851823	SCV002243732	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg218 amino acid residue in TGFB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973241, 23846138, 25099136, 30034812). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TGFB1 function (PMID: 20308061). 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 not expected to disrupt TGFB1 protein function. ClinVar contains an entry for this variant (Variation ID: 12529). This missense change has been observed in individuals with Camurati-Engelmann syndrome (PMID: 10973241, 15326622). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 218 of the TGFB1 protein (p.Arg218His).
GeneDx	RCV001851823	SCV004035573	pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant disrupts dimerization and reduces the stability of the latent TGF-beta1 complex (Walton et al., 2010); This variant is associated with the following publications: (PMID: 11810278, 20301335, 19654961, 27484238, 10973241, 24154985, 15326622, 17029195, 29184006, 29620655, 32154989, 35137278, 20308061)
Neuberg Centre For Genomic Medicine, NCGM	RCV000013355	SCV004048307	pathogenic	Diaphyseal dysplasia		criteria provided, single submitter	clinical testing	The missense variant c.653G>A (p.Arg218His) in TGFB1 gene has been reported in heterozygous state in a patient affected with Camurati-Engelmann disease. It is one of the most prevalent variants seen associated with the disease (Kim YM. et al., 2018). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Arginine at position 218 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. The variant has been previously reported in heterozygous state. Camurati Engelmann is inherited in a dominant manner. Homozygous variants have not been previously reported. The possibility of an underlying deletion leading to homozygosity cannot be overruled. Parental testing for the above variant is recommended. Further analysis for possible underlying deletion will be based on the results of the same.
Ambry Genetics	RCV004018619	SCV004965658	pathogenic	Inborn genetic diseases	2024-01-12	criteria provided, single submitter	clinical testing	The c.653G>A (p.R218H) alteration is located in exon 4 (coding exon 4) of the TGFB1 gene. This alteration results from a G to A substitution at nucleotide position 653, causing the arginine (R) at amino acid position 218 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with Camurati-Engelmann disease (CED) and has been shown to segregate with disease in large families with varying severities of CED and asymptomatic individuals (Kinoshita, 2000; Campos-Xavier, 2001; Wallace, 2004; Park, 2009; Bhadada, 2014; Hughes, 2019; Liang, 2022). Additionally, this variant has been determined to be the result of a de novo mutation in one individual with with CED (Tsang, 2020). Another alteration at the same codon, c.652C>T (p.R218C), has also been detected in individuals with CED (Liang, 2022). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000013355	SCV000033602	pathogenic	Diaphyseal dysplasia	2000-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000013355	SCV000055712	not provided	Diaphyseal dysplasia		no assertion provided	literature only