ClinVar Miner

Submissions for variant NM_000451.4(SHOX):c.440G>A (p.Arg147His)

gnomAD frequency: 0.00001  dbSNP: rs886043634
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000369436 SCV000341211 pathogenic not provided 2016-04-06 criteria provided, single submitter clinical testing
GeneDx RCV000369436 SCV005325967 uncertain significance not provided 2024-03-05 criteria provided, single submitter clinical testing Observed in multiple individuals with Leri-Weill dyschondrosteosis or idiopathic short stature in published literature, but familial segregation information and additional clinical information were not included (PMID: 17201812, 23636926, 24296787, 31219618); Not observed at 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: 17201812, 23729538, 31219618, 30743796, 24296787, 33281875, 23636926)
Clinical Genomics Laboratory, Washington University in St. Louis RCV005054189 SCV005688728 uncertain significance SHOX-related short stature 2024-01-17 criteria provided, single submitter clinical testing The SHOX c.440G>A (p.Arg147His) variant has been reported in at least seven individuals from two families affected with Leri-Weill dyschondrosteosis (Bunyan DJ et al., PMID: 23636926; Funari MFA et al., PMID: 31219618; Jorge AA et al., PMID: 17201812; Malaquias AC et al., PMID: 24296787). This variant has been reported in the ClinVar database as a germline pathogenic variant by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in a predicted alpha helix (AlphaFold) within the homeobox domain and computational predictors indicate that the variant is damaging, evidence that correlates with impact to SHOX function. Additionally, other variants in the same codon, p.Arg147Pro and p.Arg147Ser, have been reported in individuals affected with Leri-Weill dyschondrosteosis but are considered variants of uncertain significance (Bunyan DJ et al., PMID: 23636926; Rodríguez FA et al., PMID: 23729538). However, due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

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