Submissions for variant NM_000127.3(EXT1):c.1469del (p.Leu490fs)

dbSNP: rs886039356

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255784	SCV000321615	pathogenic	not provided	2021-11-17	criteria provided, single submitter	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23439489, 10679937, 29529714, 23262345, 18165274, 16088908, 9326317, 11432960, 17301954, 9150727, 9463333, 10480354, 7550340, 21039224, 29126381, 19810120, 11391482, 30334991, 30806661, 33632255, 32293802, 33552269)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702125	SCV000830961	pathogenic	Multiple congenital exostosis	2024-09-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu490Argfs*9) 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 and hereditary multiple osteochondromas (PMID: 7550340, 23439489, 29126381). 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: 265131). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001003498	SCV002577583	pathogenic	Exostoses, multiple, type 1	2022-03-24	criteria provided, single submitter	clinical testing	PVS1, PM2, PP3, PP5
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001003498	SCV003799045	pathogenic	Exostoses, multiple, type 1	2022-12-14	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2, PM6
Institute of Human Genetics, University Hospital of Duesseldorf	RCV001003498	SCV004046799	pathogenic	Exostoses, multiple, type 1		criteria provided, single submitter	not provided
Baylor Genetics	RCV004567807	SCV005060409	pathogenic	Chondrosarcoma	2023-12-12	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001003498	SCV005073943	pathogenic	Exostoses, multiple, type 1		criteria provided, single submitter	clinical testing	The observed frameshift variant c.1469del (p.Leu490ArgfsTer9) in EXT1 gene has been reported in heterozygous state in multiple individuals affected with Exostoses (Kim S et al. 2022; Mohaidat Z et al. 2021; Santos SCL et al. 2018). The p.Leu490ArgfsTer9 variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Leucine 490, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Leu490ArgfsTer9. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in EXT1 are known to be pathogenic (Jennes I et al. 2009). For these reasons, this variant has been classified as Pathogenic
Department of Human Genetics, Hannover Medical School	RCV001003498	SCV005088712	pathogenic	Exostoses, multiple, type 1	2024-07-30	criteria provided, single submitter	clinical testing
OMIM	RCV001003498	SCV000022756	pathogenic	Exostoses, multiple, type 1	1995-10-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001003498	SCV001133029	pathogenic	Exostoses, multiple, type 1	2019-09-26	no assertion criteria provided	clinical testing