Submissions for variant NM_014846.4(WASHC5):c.1178G>A (p.Arg393His)

gnomAD frequency: 0.00016  dbSNP: rs151298198

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000685841	SCV000813340	uncertain significance	Hereditary spastic paraplegia 8; Ritscher-Schinzel syndrome	2023-06-16	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WASHC5 protein function. ClinVar contains an entry for this variant (Variation ID: 566111). This missense change has been observed in individual(s) with spastic paraplegia (PMID: 31814071). This variant is present in population databases (rs151298198, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 393 of the WASHC5 protein (p.Arg393His).
Illumina Laboratory Services, Illumina	RCV001163529	SCV001325581	likely benign	Hereditary spastic paraplegia 8	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001574559	SCV001801403	uncertain significance	not provided	2023-10-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31814071)
Ambry Genetics	RCV002544726	SCV003694996	uncertain significance	Inborn genetic diseases	2022-05-27	criteria provided, single submitter	clinical testing	Unlikely to be causative of WASHC5-related spastic paraplegia (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV001574559	SCV004163195	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing