ClinVar Miner

Submissions for variant NM_022173.4(TIA1):c.1150G>A (p.Glu384Lys) (rs747068278)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000267511 SCV000330041 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing The E384K pathogenic variant in the TIA1 gene is a founder mutation found in individuals with Welander distal myopathy of Swedish and Finnish descent (Hackman et al., 2013; Klar et al., 2013). The E384K variant is observed in 8/111,666 (0.007%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The E384K missense variant has not been shown to significantly alter mRNA levels of TIA1 (Klar et al., 2013), however, functional studies demonstrate a damaging effect for the E384K variant with a mild but consistent increase in stress granule abundance compared to wild type (Hackman et al., 2013). The E384K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret E384K as a pathogenic variant.
Invitae RCV000576901 SCV000964805 pathogenic Welander distal myopathy 2019-08-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 384 of the TIA1 protein (p.Glu384Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs747068278, ExAC 0.01%). This variant has been observed to segregate with Welander distal myopathy (WDM) in many families and is considered a founder mutation in the Swedish and Finnish population (PMID: 10482271, 23401021, 27282841, 23348830). ClinVar contains an entry for this variant (Variation ID: 41480). Experimental studies have shown that this missense change alters stress granule disassembly, mobility, and solubility (PMID: 28817800, 23401021). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000267511 SCV001450108 pathogenic not provided 2014-07-01 criteria provided, single submitter clinical testing
OMIM RCV000576901 SCV000678313 pathogenic Welander distal myopathy 2013-04-01 no assertion criteria provided literature only

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