Submissions for variant NM_000127.3(EXT1):c.1019G>A (p.Arg340His)

dbSNP: rs119103287

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254839	SCV000321613	pathogenic	not provided	2021-10-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 11391482, 10713884, 26239617, 24532482, 19810120, 23439489, 9521425, 11170095, 26961984, 25468659, 33414810, 30334991, 30806661, 34006472, 33552269)
Invitae	RCV000630812	SCV000751779	pathogenic	Multiple congenital exostosis	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 340 of the EXT1 protein (p.Arg340His). This variant is present in population databases (rs119103287, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary multiple osteochondromas, also known as hereditary multiple exostoses (PMID: 9521425, 10713884, 19810120, 23439489, 24532482, 25468659, 26239617, 26961984). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265129). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EXT1 protein function. Experimental studies have shown that this missense change affects EXT1 function (PMID: 11391482). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001263553	SCV002521833	pathogenic	Exostoses, multiple, type 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265129). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:19810120). Different missense changes at the same codon (p.Arg340Cys, p.Arg340Gly, p.Arg340Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002495, VCV000002500, VCV000988576). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000254839	SCV004026144	pathogenic	not provided	2021-06-22	criteria provided, single submitter	clinical testing	PP4, PP5, PS4, PM2_SUP, PP1
OMIM	RCV001263553	SCV001441614	pathogenic	Exostoses, multiple, type 1	2020-11-06	no assertion criteria provided	literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000630812	SCV001482330	pathogenic	Multiple congenital exostosis	2019-05-31	no assertion criteria provided	research