rs119103290

Positions:

• chr8-117837146-G-A
• chr8-117837146-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000127.3(EXT1):​c.1018C>T​(p.Arg340Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,746 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EXT1 NM_000127.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.71

Genes affected

EXT1 (HGNC:3512): (exostosin glycosyltransferase 1) This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of multiple exostoses. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000127.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-117837146-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 988576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 8-117837146-G-A is Pathogenic according to our data. Variant chr8-117837146-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117837146-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-117837146-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.1018C>T	p.Arg340Cys	missense_variant	2/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1018C>T	p.Arg340Cys	missense_variant	2/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.485C>T		non_coding_transcript_exon_variant	2/11
EXT1	ENST00000436216.2	c.388C>T	p.Arg130Cys	missense_variant, NMD_transcript_variant	2/6	3
EXT1	ENST00000437196.1	c.74-1595C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461746 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000599 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2023	Published functional studies demonstrate an almost complete loss of glycosyltransferase activity of the EXT1/EXT2 complex involved in the polymerization of heparan sulfate (McCormick et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11170095, 15586175, 16088908, 10679937, 17301954, 10679296, 9326317, 10639137, 25230886, 9620772, 20418910, 11391482, 9521425, 11432960, 26239617, 19810120, 26961984, 18165274, 8981950, 30806661, 33726816) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 07, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2021

The c.1018C>T (p.R340C) alteration is located in exon 2 (coding exon 2) of the EXT1 gene. This alteration results from a C to T substitution at nucleotide position 1018, causing the arginine (R) at amino acid position 340 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple unrelated patients with multiple osteochondromas (Philippe, 1997; Francannet, 2001; Ciavarella, 2013). Other alterations affecting the same arginine at amino acid position 340 have also been reported in affected patients (Hecht, 1997; Raskind, 1998; Wuyts, 1998; Jennes, 2009). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Multiple congenital exostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 340 of the EXT1 protein (p.Arg340Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple osteochondromas/exostoses (PMID: 9326317, 11432960, 16283885, 20418910, 22258776, 25230886). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2500). 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 EXT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EXT1 function (PMID: 9620772, 10639137, 10679296). This variant disrupts the p.Arg340 amino acid residue in EXT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8981950, 9521425, 11391482, 18165274, 18330718, 19810120, 26239617, 26961984). 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. -

Exostoses, multiple, type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1998

- -

EXT1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2024

The EXT1 c.1018C>T variant is predicted to result in the amino acid substitution p.Arg340Cys. This variant has been reported to be causative for hereditary multiple osteochondromas, and in at least one instance was found to be de novo (see, for example, Philippe et al. 1997. PubMed ID: 9326317; Francannet et al. 2001. PubMed ID: 11432960; Stranneheim et al. 2021. PubMed ID: 33726816). An in vitro functional study demonstrates that expression of this variant disrupts EXT1 function (McCormick et al. 1998. PubMed ID: 9620772). This variant is not present in a large population database, indicating this variant is rare. The p.Arg340 codon is a hotspot for EXT1 pathogenic variants (Jennes et al. 2009. PubMed ID: 19810120; Fusco et al. 2019. PubMed ID: 30806661). This variant has been consistently interpreted as pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/2500/). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.85		Loss of methylation at R340 (P = 0.0346);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.67
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs119103290; hg19: chr8-118849385;