Submissions for variant NM_012210.4(TRIM32):c.1181G>A (p.Arg394His)

gnomAD frequency: 0.00002  dbSNP: rs121434447

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000362326	SCV000334258	uncertain significance	not provided	2015-09-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638363	SCV000759862	likely pathogenic	Bardet-Biedl syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 394 of the TRIM32 protein (p.Arg394His). This variant is present in population databases (rs121434447, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 17994549; Invitae). ClinVar contains an entry for this variant (Variation ID: 7353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TRIM32 function (PMID: 17994549, 19349376, 33296226). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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
PreventionGenetics, part of Exact Sciences	RCV004748510	SCV005361173	likely pathogenic	TRIM32-related disorder	2024-04-15	no assertion criteria provided	clinical testing	The TRIM32 c.1181G>A variant is predicted to result in the amino acid substitution p.Arg394His. This variant has been reported in the homozygous state in two patients with limb-girdle muscular dystrophy-8 (LGMDR8) (Table 1 and Figure S3, Saccone et al. 2008. PubMed ID: 17994549; Table S2, Johnson et al. 2018. PubMed ID: 29921608). It has also been reported as a single heterozygous variant and together with another missense variant (phase unknown) in a LGMDR8 patient (Rimoldi et al. 2024. PubMed ID: 38304327). The affected amino acid is located in one of the NHL domains where LGMD2H causative variants cluster. Functional assays suggest that this variant impairs protein function (Saccone et al. 2008. PubMed ID: 17994549; Locke et al. 2009. PubMed ID: 19349376; Bawa et al. 2021. PubMed ID: 33296226). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.