Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000697805 | SCV000826436 | likely pathogenic | Autosomal recessive distal spinal muscular atrophy 2; Amyotrophic lateral sclerosis type 16 | 2023-05-30 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 575556). This missense change has been observed in individuals with distal hereditary motor neuropathy (PMID: 27629094, 28708278; Invitae). This variant is present in population databases (rs140376902, gnomAD 0.005%). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 65 of the SIGMAR1 protein (p.Leu65Gln). 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. 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. |
| Victorian Clinical Genetics Services, |
RCV002272335 | SCV002557317 | pathogenic | Amyotrophic lateral sclerosis type 16 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spinal muscular atrophy, distal, autosomal recessive, 2 (MIM#605726), and is a likely mechanism for amyotrophic lateral sclerosis 16, juvenile (MIM#614373) (PMID: 31511340, PMID: 25704016). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ERG2_Sigma1R domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic, and observed in a homozygous individual with distal hereditary motor neuropathy and/or Silver-like syndrome (ClinVar, PMID: 27629094, PMID: 28708278). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |