8-117819743-AGGG-AGGGG

Variant names:

• chr8-117819743-A-AG
• rs886039355
• NM_000127.3:c.1468dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000127.3(EXT1):​c.1468dupC​(p.Leu490ProfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT1 NM_000127.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.06
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• exostoses, multiple, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• chondrosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hereditary multiple osteochondromas

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-117819743-A-AG is Pathogenic according to our data. Variant chr8-117819743-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 279804.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.1468dupC	p.Leu490ProfsTer31	frameshift_variant	Exon 6 of 11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.1468dupC	p.Leu490ProfsTer31	frameshift_variant	Exon 6 of 11	1	NM_000127.3	ENSP00000367446.3
EXT1	ENST00000437196.1	n.*359dupC		non_coding_transcript_exon_variant	Exon 5 of 10	5		ENSP00000407299.1
EXT1	ENST00000684189.1	n.935dupC		non_coding_transcript_exon_variant	Exon 6 of 11
EXT1	ENST00000437196.1	n.*359dupC		3_prime_UTR_variant	Exon 5 of 10	5		ENSP00000407299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Pathogenic:2

Mar 22, 2021

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu490Profs*31) in the EXT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT1 are known to be pathogenic (PMID: 10679937, 11391482, 19810120). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with multiple osteochondromas (PMID: 11170095, 15586175, 17301954, 18165274). Invitae’s hereditary multiple osteochondromas clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this EXT1 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 50,122 individuals referred for testing at Invitae. This variant is also known as c.1468insC, c.1469insC, and c.1468-1469insC. ClinVar contains an entry for this variant (Variation ID: 279804). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15586175, 16283885, 19810120, 28922105, 18165274, 9150727, 11170095, 17301954, 23262345, 31096510, 32619249, 36703223, 30332465) -

Chondrosarcoma;CN263289:Exostoses, multiple, type 1 Pathogenic:1

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Exostoses, multiple, type 1 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift duplication p.L490Pfs*31 in EXT1 (NM_000127.3) has been reported previously in individuals affected with Hereditary multiple exostoses (Seki et al, 2001; Signori et al, 2007). This variant causes a frameshift starting with codon Leucine 490, changes this amino acid to Proline residue, and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Leu490ProfsTer31. The p.L490Pfs*31 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 31 residues until a stop codon is reached. The p.L490Pfs*31 variant is a loss of function variant in the gene EXT1, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886039355; hg19: chr8-118831982;