Submissions for variant NM_207122.2(EXT2):c.1022C>T (p.Pro341Leu)

gnomAD frequency: 0.00044  dbSNP: rs141035971

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000795903	SCV000371844	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000766600	SCV000576979	uncertain significance	not provided	2022-02-18	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with EXT2-related disorders to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28384719, 27535533, 28166811, 24728327)
Fulgent Genetics, Fulgent Genetics	RCV000763739	SCV000894624	uncertain significance	Exostoses, multiple, type 2; Seizures-scoliosis-macrocephaly syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000795903	SCV000935384	uncertain significance	Exostoses, multiple, type 2	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 341 of the EXT2 protein (p.Pro341Leu). This variant is present in population databases (rs141035971, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134215). 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 EXT2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000795903	SCV002525986	uncertain significance	Exostoses, multiple, type 2	2023-10-18	criteria provided, single submitter	clinical testing	The EXT2 c.1121C>T (p.Pro374Leu) missense change has a maximum subpopulation frequency of 0.050% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary multiple exostoses. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
ITMI	RCV000120888	SCV000085056	not provided	not specified	2013-09-19	no assertion provided	reference population
GenomeConnect, ClinGen	RCV000795903	SCV001423440	not provided	Exostoses, multiple, type 2		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.