Submissions for variant NM_014846.4(WASHC5):c.2097+6A>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699941	SCV005205078	uncertain significance	not specified	2024-06-06	criteria provided, single submitter	clinical testing	Variant summary: KIAA0196 c.2097+6A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 282744 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2097+6A>G in individuals affected with Ritscher-Schinzel Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005216306	SCV005855339	uncertain significance	Hereditary spastic paraplegia 8; Ritscher-Schinzel syndrome	2024-07-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the WASHC5 gene. It does not directly change the encoded amino acid sequence of the WASHC5 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WASHC5-related conditions. 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 is not likely to affect RNA splicing. 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.