ClinVar Miner

Submissions for variant NM_000127.2(EXT1):c.1019G>A (p.Arg340His) (rs119103287)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254839 SCV000321613 pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing The R340H variant has been published previously in association with hereditary multiple exostoses, including as an apparently de novo occurrence (Raskind et al., 1998; Sarrión et al., 2013). It has also been observed to occur apparently de novo in an affected individual at GeneDx. The variant is observed in 1/111416 (0.0009%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies have shown R340H results in protein inactivity (Cheung et al., 2001). Missense variants in the same residue (R340C/S/G/L/P) and in nearby residues (L335R, P337R, G339V/D, R341G/S, G343R/W, S344F) have been reported in the Human Gene Mutation Database in association with multiple exostoses (Stenson et al., 2014), supporting the functional importance of this region of the protein. We consider this variant to be pathogenic.
Invitae RCV000630812 SCV000751779 pathogenic Multiple congenital exostosis 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 340 of the EXT1 protein (p.Arg340His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs119103287, ExAC 0.002%). This is one of the most frequently reported EXT1 variants in individuals affected with hereditary multiple osteochondromas, also known as hereditary multiple exostoses (PMID: 19810120). It has been reported in the literature to segregate with disease in multiple families and individuals (PMID: 9521425, 23439489, 24532482, 25468659, 26961984, 26239617, 10713884). In addition, this variant has been shown to be de novo in at least one of these affected individuals (PMID: 9521425). It is also known as c.1670G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 265129). Experimental studies have shown that this missense change disrupts the protein function of EXT1 in cell culture (PMID: 11391482). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV001263553 SCV001441614 pathogenic Multiple exostoses 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

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