NM_000127.3:c.1018C>G

Variant names:

• chr8-117837146-G-C
• rs119103290
• NM_000127.3:c.1018C>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000127.3(EXT1):​c.1018C>G​(p.Arg340Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R340S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 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, 0.94
• PP5: Variant 8-117837146-G-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT1	NM_000127.3	c.1018C>G	p.Arg340Gly	missense_variant	Exon 2 of 11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.1018C>G	p.Arg340Gly	missense_variant	Exon 2 of 11	1	NM_000127.3	ENSP00000367446.3
EXT1	ENST00000436216.2	n.385C>G		non_coding_transcript_exon_variant	Exon 2 of 6	3		ENSP00000400372.1
EXT1	ENST00000684189.1	n.485C>G		non_coding_transcript_exon_variant	Exon 2 of 11
EXT1	ENST00000437196.1	n.74-1595C>G		intron_variant	Intron 1 of 9	5		ENSP00000407299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Pathogenic:1

Jun 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: 9521425, 26239617, 26961984). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 988576). This missense change has been observed in individual(s) with hereditary multiple osteochondromas, also known as hereditary multiple exostoses (PMID: 28600779, 33726816). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 340 of the EXT1 protein (p.Arg340Gly). -

not provided Pathogenic:1

Sep 23, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Exostoses, multiple, type 1 Pathogenic:1

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.75		Gain of methylation at R341 (P = 0.0325);
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.92

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

Other links and lift over

dbSNP: rs119103290; hg19: chr8-118849385;