Submissions for variant NM_012470.4(TNPO3):c.2767del (p.Arg923fs)

dbSNP: rs1563083759

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000778113	SCV001228651	likely pathogenic	Autosomal dominant limb-girdle muscular dystrophy type 1F	2022-03-09	criteria provided, single submitter	clinical testing	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. This variant results in an extension of the TNPO3 protein. Other variant(s) that result in a similarly extended protein product (p.*924Cysext*15) have been determined to be pathogenic (PMID: 23543484, 23667635). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 591000). This frameshift has been observed in at least one individual who was not affected with TNPO3-related conditions (Invitae). This frameshift has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 31071488, 31217819). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the TNPO3 gene (p.Arg923Aspfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the TNPO3 protein and extend the protein by 15 additional amino acid residues.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV004797620	SCV005419095	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant	2024-11-21	criteria provided, single submitter	curation	The heterozygous p.Arg923AspfsTer17 variant was identified by our study in 2 affected siblings with limb-girdle muscular dystrophy. The p.Arg923AspfsTer17 variant has been reported in 2 affected individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 31071488). This variant was absent from large population studies. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 591000) and has been interpreted as likely pathogenic by Labcorp and Department of Medical Genetics (University of Pecs). This variant causes a frameshift which abolishes the native stop codon and extends the protein an additional 15 amino acids. Other c-terminal extending proteins in TNPO3 have been seen in individuals with limb-girlde muscular dystrophy (PMID: 23543484). Heterozygous loss of function of the TNPO3 gene is an established disease mechanism in limb-girdle muscular dystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant limb-girdle muscular dystrophy. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting, PS4_supporting (Richards 2015).
Department of Medical Genetics, University of Pecs	RCV000778113	SCV000853236	likely pathogenic	Autosomal dominant limb-girdle muscular dystrophy type 1F	2018-09-10	no assertion criteria provided	clinical testing	The c.2767delC (p.Arg923Aspfs*17) variant was predicted to cause truncated protein. Other dominant truncating mutations in the TNPO3 protein are reported to cause Limb-Girdle Muscular Dystrophy type 1F (LGMD1F) (Gamez J. et al. 2001). Segregation analysis confirmed that the same variant is seen in the patient's affected son, and absent in her unaffected son. The variant has not been previously seen in presumed healthy control databases (ExAC, 1000Genomes, EVS).