Submissions for variant NM_207122.2(EXT2):c.260T>G (p.Met87Arg)

gnomAD frequency: 0.00031  dbSNP: rs140075817

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000988530	SCV000371829	benign	Exostoses, multiple, type 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988530	SCV001100588	benign	Exostoses, multiple, type 2	2025-01-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000988530	SCV001138278	likely benign	Exostoses, multiple, type 2	2021-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001705882	SCV001813674	likely benign	not provided	2021-03-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26246518)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001705882	SCV002009175	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120884	SCV005726551	uncertain significance	not specified	2024-11-19	criteria provided, single submitter	clinical testing	Variant summary: EXT2 c.260T>G (p.Met87Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EXT2 causing Seizures, Scoliosis, And Macrocephaly Syndrome, allowing no conclusion about variant significance. c.260T>G has been reported in the literature in the homozygous state in cis with another variant of uncertain significance in four related individuals affected with Seizures, Scoliosis, And Macrocephaly Syndrome without osteochondromas reported in the family and has also been reported without strong evidence for causality in at least one individual with multiple osteochondromas (e.g. Farhan_2015, Gnoli_2024). These reports do not provide unequivocal conclusions about association of the variant with Seizures, Scoliosis, And Macrocephaly Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in >75%-90% of WT protein expression in vitro (Farhan_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26246518, 38351015). ClinVar contains an entry for this variant (Variation ID: 134211). Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI	RCV000120884	SCV000085052	not provided	not specified	2013-09-19	no assertion provided	reference population