Submissions for variant NM_000454.5(SOD1):c.357+2dup

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003121938	SCV003789142	uncertain significance	Amyotrophic lateral sclerosis type 1	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the SOD1 gene. It does not directly change the encoded amino acid sequence of the SOD1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs747768384, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SOD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2420773). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004747265	SCV005361922	uncertain significance	SOD1-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The SOD1 c.357+2dupT variant is predicted to result in an intronic duplication. This variant is predicted to create a cryptic splice site based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), however, such computer prediction programs are imperfect. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.