Submissions for variant NM_014946.4(SPAST):c.1413+3_1413+6del

dbSNP: rs570685843

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000644896	SCV000766614	likely pathogenic	Hereditary spastic paraplegia 4	2022-08-07	criteria provided, single submitter	clinical testing	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. This variant disrupts the c.1413+5G nucleotide in the SPAST gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 536445). This variant is also known as c.1538+3del4. This variant has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 10699187, 26671083). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the SPAST gene. It does not directly change the encoded amino acid sequence of the SPAST protein. It affects a nucleotide within the consensus splice site.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000644896	SCV001367835	pathogenic	Hereditary spastic paraplegia 4	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3.
Paris Brain Institute, Inserm - ICM	RCV000644896	SCV001450986	pathogenic	Hereditary spastic paraplegia 4		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000644896	SCV002767447	pathogenic	Hereditary spastic paraplegia 4	2021-05-06	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: 0103 - Dominant Negative and loss-of-function are known mechanisms of disease for this gene and are associated with spastic paraplegia 4 (MIM#182601). Multiple loss of function variants have been reported, while a dominant negative mechanism has been stipulated for a small number of missense variants (ClinVar; PMID: 30006150). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, but this is age-dependant and only a small proportion of individuals remain asymptomatic (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity, with variable age of onset and disease severity (PMID: 30476002). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other splice variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Many different variants affecting the deleted nucleotides of this variant (c.1413+5G>C, c.1413+5G>A, c.1413+4A>G, c.1413+3A>C and c.1413+6T>C) have been reported as pathogenic and likely pathogenic in patients with hereditary spastic paraplegia (ClinVar, PMID: 30375765). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, in multiple patients with hereditary spastic paraplegia (ClinVar, PMID: 10699187, PMID: 26671083, PMID: 15841487, PMID: 23252998). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign