rs104894721

Positions:

• chr19-41342230-G-A

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.652C>T​(p.Arg218Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,608 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. R218H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.07

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]

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, 0.924
• PP5: Variant 19-41342230-G-A is Pathogenic according to our data. Variant chr19-41342230-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12531.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.652C>T	p.Arg218Cys	missense_variant	4/7	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.652C>T	p.Arg218Cys	missense_variant	4/7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.652C>T	p.Arg218Cys	missense_variant	4/7	1	NM_000660.7	ENSP00000221930	P1
TGFB1	ENST00000597453.1	n.183C>T		non_coding_transcript_exon_variant	3/3	1
TGFB1	ENST00000600196.2	c.652C>T	p.Arg218Cys	missense_variant	4/6	5		ENSP00000504008
TGFB1	ENST00000677934.1	c.634+2517C>T		intron_variant				ENSP00000504769

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449608 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720222

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diaphyseal dysplasia Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Camurati-Engelmann disease (MIM#131300). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Inter- and intra-familial clinical variability has been reported (PMIDs: 30721323, 35315241). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated latency associated peptide domain (PMID: 30721323). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories (ClinVar) and has been identified in multiple individuals with a diagnosis of Camurati-Engelmann disease (PMIDs: 10973241, 17206397, 35415221). Additionally, this variant has been described as one of three recurrent pathogenic variants identified in multiple families of different ethnic backgrounds (PMID: 30721323). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. A mutant construct harbouring this variant and transfected in HEK293T cells demonstrated increased luciferase activity due to elevated levels of active TGF-B1 protein compared to the WT construct (PMID: 12493741). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2021	Reported previously as the most frequently identified variant among families with Camurati-Engelmann disease (Kinoshita et al., 2004); Published functional studies demonstrate that this variant disrupts dimerization and reduces the stability of the latent TGF-beta 1 complex (Walton et al., 2010); Not observed in large population cohorts (Lek et al., 2016); 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: 28943142, 15103729, 25099136, 23846138, 10973241, 11062463, 30034812, 29620655, 12843182, 20308061) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TGFB1: PS2, PM2, PM5, PP1, PP4, PS3:Supporting, PS4:Supporting, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 218 of the TGFB1 protein (p.Arg218Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Camurati-Engelmann syndrome (PMID: 10973241, 23846138, 25099136, 30034812). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12531). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TGFB1 function (PMID: 19584867). For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Vest4		0.90
MutPred		0.73		Gain of catalytic residue at S220 (P = 0.0398);
MVP		0.87
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104894721; hg19: chr19-41848135;