ClinVar Miner

Submissions for variant NM_001365068.1(ASTN2):c.2806+26570C>T (rs111033570)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414917 SCV000492867 pathogenic Myopathy 2015-04-08 criteria provided, single submitter clinical testing
Invitae RCV000538874 SCV000636501 pathogenic Bardet-Biedl syndrome 2020-02-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 487 of the TRIM32 protein (p.Asp487Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with limb-girdle muscular dystrophy type 2H and sarcotubular myopathy in multiple families (PMID: 23142638, 15786463, 11822024). It is a common cause of these disorders in individuals of Hutterite ancestry. ClinVar contains an entry for this variant (Variation ID: 7350). Experimental studies have shown that this missense leads to greatly reduced TRIM32 protein levels and neuromuscular disease in transgenic mice (PMID: 21775502). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000007775 SCV001164476 pathogenic Sarcotubular myopathy 2018-12-03 criteria provided, single submitter research The homozygous p.Asp487Asn variant in TRIM32 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.001791% (2/111664) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs111033570). 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 do not provide strong support for or against an impact to the protein. The p.Asp487Asn variant in TRIM32 has been reported in 55 Hutterite individuals with LGMD and segregated with disease in 8 affected relatives from 3 families (PMID: 11822024, 15786463). Animal models in mice have shown that this variant causes Limb-Girdle Muscular Dystrophy by lowering protein stability but not mRNA levels. Knock-in mice with this variant showed a similar neuromuscular phenotype to trim32 knock-out mice, supporting pathogenicity as a loss of function variant (PMID: 21775502). This variant has also been reported pathogenic in ClinVar by multiple submitters (Variation ID: 7350). In summary, the p.Asp487Asn variant is pathogenic. ACMG/AMP Criteria applied: PM2, PP1_Strong, PS3 (Richards 2015).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198489 SCV001369440 pathogenic Bardet-Biedl syndrome 11 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. This variant was detected in homozygous state.
OMIM RCV000007775 SCV000027976 pathogenic Sarcotubular myopathy 2012-10-05 no assertion criteria provided literature only

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