Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000805664 | SCV000945630 | pathogenic | Autosomal recessive distal spinal muscular atrophy 2; Amyotrophic lateral sclerosis type 16 | 2023-03-01 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg7Glyfs*16) in the SIGMAR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SIGMAR1 are known to be pathogenic (PMID: 26078401, 27402882, 28708278, 29115704). This variant is present in population databases (rs747285235, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hereditary motor neuropathy (PMID: 28708278). This variant is also known as c.18delC (p.G6Afs*17). ClinVar contains an entry for this variant (Variation ID: 650504). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002422760 | SCV002724190 | likely pathogenic | Inborn genetic diseases | 2022-02-28 | criteria provided, single submitter | clinical testing | The c.19delC variant, located in coding exon 1 of the SIGMAR1 gene, results from a deletion of one nucleotide at nucleotide position 19, causing a translational frameshift with a predicted alternate stop codon (p.R7Gfs*16). The predicted stop codon occurs within the first 150 nucleotides of theSIGMAR1 gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). However, a significant portion of the protein is affected (Ambry internal data). This variant was detected alongside another variant in SIGMAR1 in an individual with progressive weakness in the lower extremities; nerve conduction studies for this individual revealed a prolonged terminal motor latency (Hartley T et al. Clin Genet, 2018 02;93:301-309). Based on data from gnomAD, this allele has an overall frequency of 0.002% (4/160174) total alleles studied. The highest observed frequency was 0.006% (4/63174) of European (non-Finnish) alleles. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |