rs104894720

Positions:

• chr19-41342229-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000660.7(TGFB1):​c.653G>A​(p.Arg218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 2.45

Genes affected

TGFB1 (HGNC:11766): (transforming growth factor beta 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TGFB1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_000660.7 (TGFB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a strand (size 15) in uniprot entity TGFB1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000660.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 19-41342229-C-T is Pathogenic according to our data. Variant chr19-41342229-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.653G>A	p.Arg218His	missense_variant	4/7	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.653G>A	p.Arg218His	missense_variant	4/7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.653G>A	p.Arg218His	missense_variant	4/7	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000597453.1	n.184G>A		non_coding_transcript_exon_variant	3/3	1
TGFB1	ENST00000600196.2	c.653G>A	p.Arg218His	missense_variant	4/6	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.634+2518G>A		intron_variant				ENSP00000504769.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1449734 Hom.: 0 Cov.: 33 AF XY: 0.00000278 AC XY: 2 AN XY: 720288

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: 0.00000271

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diaphyseal dysplasia Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	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). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.34	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.029	D
Vest4		0.91
MutPred		0.74		Gain of sheet (P = 0.1451);
MVP		0.86
MPC		1.9
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104894720; hg19: chr19-41848134;