Submissions for variant NM_000127.3(EXT1):c.1468dup (p.Leu490fs)

dbSNP: rs886039355

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000309326	SCV000329342	pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing	This variant has been reported previously in association with hereditary multiple exostoses (Wells et al., 1997; Seki et al., 2001; Signori et al., 2007). The c.1468dupC variant causes a frameshift starting with codon Leucine 490, changes this amino acid to a Proline residue and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Leu490ProfsX31. The duplication follows a polycytosine tract which is a hot spot for pathogenic variants. Frameshift variants starting from codon Leucine 490 have been observed in 7% of patients with an EXT1-related disorder (Jennes et al., 2009). The c.1468dupC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense mediated mRNA decay.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697332	SCV000825934	pathogenic	Multiple congenital exostosis	2024-04-15	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV002487173	SCV002791633	pathogenic	Chondrosarcoma; Exostoses, multiple, type 1	2021-08-20	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000309326	SCV002818213	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338493	SCV004048295	pathogenic	Exostoses, multiple, type 1		criteria provided, single submitter	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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000697332	SCV001984167	pathogenic	Multiple congenital exostosis	2021-03-22	flagged submission	clinical testing