8-117837145-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000127.3(EXT1):c.1019G>A(p.Arg340His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,710 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R340S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EXT1
NM_000127.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.90

Variant links:

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]

EXT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

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, 0.943

PP5

Variant 8-117837145-C-T is Pathogenic according to our data. Variant chr8-117837145-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-117837145-C-T is described in Lovd as [Likely_pathogenic]. Variant chr8-117837145-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT1	NM_000127.3 link	c.1019G>A	p.Arg340His	missense_variant	Exon 2 of 11	ENST00000378204.7	NP_000118.2	Q16394

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXT1	ENST00000378204.7 link	c.1019G>A	p.Arg340His	missense_variant	Exon 2 of 11	1	NM_000127.3	ENSP00000367446.3	Q16394
EXT1	ENST00000436216.2 link	n.386G>A		non_coding_transcript_exon_variant	Exon 2 of 6	3		ENSP00000400372.1	H7C1H6
EXT1	ENST00000684189.1 link	n.486G>A		non_coding_transcript_exon_variant	Exon 2 of 11
EXT1	ENST00000437196.1 link	n.74-1594G>A		intron_variant	Intron 1 of 9	5		ENSP00000407299.1	F8WF54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251146

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital exostosis

Pathogenic:3

Sep 01, 2024

Suzhou Clinical Center for Rare Diseases in Children, Children's Hospital of Soochow University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000127.3:c.1019G>A(p.Arg340His) variant of EXT1 is a missense variant that a de novo variant both found in our patient (PS2). This variant has been identified in multiple cases of osteochondromas (PMID:10713884, 11391482, 19810120, 24532482, 25468659, 26239617, 33552269,9521425)(PS4). The gnomAD database does not include this variant's frequency in the population (PM2_Supporting). This variant results in a different amino acid change than the pathogenic variant c.1019G>T(p.R340L) at the same position (PM5). According to the literature, this variant co-segregates with the disease in family (PMID: 33552269)(PP1). Revel score is 0.84 (PP3_Moderate). According to the ACMG guidelines, this variant is interpreted as pathogenic (PS2+PS4+PM2_Supporting +PM5+PP1+PP3). -

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 340 of the EXT1 protein (p.Arg340His). This variant is present in population databases (rs119103287, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary multiple osteochondromas, also known as hereditary multiple exostoses (PMID: 9521425, 10713884, 19810120, 23439489, 24532482, 25468659, 26239617, 26961984). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this EXT1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 50,122 individuals referred to our laboratory for EXT1 testing. ClinVar contains an entry for this variant (Variation ID: 265129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EXT1 protein function. Experimental studies have shown that this missense change affects EXT1 function (PMID: 11391482). For these reasons, this variant has been classified as Pathogenic. -

Exostoses, multiple, type 1

Pathogenic:3

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265129). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:19810120). Different missense changes at the same codon (p.Arg340Cys, p.Arg340Gly, p.Arg340Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002495, VCV000002500, VCV000988576). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 21, 2025

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: PS3_Supporting, PS4_Moderate, PM1, PM6, PP3_Moderate, PP1, PP4_Strong -

Nov 06, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Jun 22, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PP5, PS4, PM2_SUP, PP1 -

Oct 27, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); 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: 11391482, 10713884, 26239617, 24532482, 19810120, 23439489, 9521425, 11170095, 26961984, 25468659, 33414810, 30334991, 30806661, 34006472, 33552269) -

EXT1-related disorder

Pathogenic:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The EXT1 c.1019G>A variant is predicted to result in the amino acid substitution p.Arg340His. This variant has been reported to be causative for hereditary multiple osteochondromas (Sarrión et al. 2013. PubMed ID: 23439489; Jamsheer et al. 2014. PubMed ID: 24532482; Ishimaru et al. 2016. PubMed ID: 26961984). Functional studies on the variant have determined its role in decreased arteriolar endothelial glycocalyx, improved flow-mediated dilation, resulting in inactive protein production (Cheung et al. 2001. PubMed ID: 11391482; Mooij et al. 2014. PubMed ID: 25468659). The Arg340 residue, located within “Exostosin-like” domain of the EXT1 protein, has been highly conserved during evolution (Alamut Visual v2.11). Of note, there are reports of other pathogenic variants (p.Arg340Ser, p.Arg340Gly, p.Arg340Cys, p.Arg340Pro, p.Arg340Leu) involving the same amino acid residue of EXT1 (HGMD, Human Gene Mutation Database). Taken together, we interpret this variant as pathogenic. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.3

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.84

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.95

Vest4

0.89

MutPred

0.81

Loss of methylation at R340 (P = 0.0346);

MVP

0.96

MPC

0.81

ClinPred

0.93

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over