ClinVar Miner

Submissions for variant NM_001365068.1(ASTN2):c.2806+26848C>T (rs121434447)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000362326 SCV000334258 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing
Invitae RCV000638363 SCV000759862 uncertain significance Bardet-Biedl syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 394 of the TRIM32 protein (p.Arg394His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121434447, ExAC 0.03%). This variant has been reported in the homozygous and heterozygous state in individuals affected with limb-girdle muscular dystrophy (PMID: 17994549). ClinVar contains an entry for this variant (Variation ID: 7353). Experimental studies have shown that this missense change disrupts TRIM32 homodimerization, enzymatic activity, and sub-cellular distribution in vitro (PMID: 17994549, 19349376). 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.
Broad Institute Rare Disease Group, Broad Institute RCV000007778 SCV001164486 uncertain significance Sarcotubular myopathy 2018-12-03 criteria provided, single submitter research The heterozygous p.Arg394His variant in TRIM32 was identified by our study in the compound heterozygous state, with a VUS, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.003658% (9/246046) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434447). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Arg394His variant may impact protein function by affecting its localization, homodimerization, and ubiquitin ligase activity (PMID: 19349376, 17994549). However, these types of assays may not accurately represent biological function. The p.Arg394His variant in TRIM32 has been reported in 2 individuals with LGMD in the literature (PMID: 17994549). This variant has also been reported in ClinVar (Variation ID: 7353). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate (Richards 2015).
Baylor Genetics RCV001334685 SCV001527598 uncertain significance Bardet-Biedl syndrome 11 2018-02-13 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000007778 SCV000027979 pathogenic Sarcotubular myopathy 2009-07-01 no assertion criteria provided literature only

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