Submissions for variant NM_014946.4(SPAST):c.870+1G>T

dbSNP: rs1553314978

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198064	SCV001368849	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,PP5,PP4,PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001198064	SCV001585386	pathogenic	Hereditary spastic paraplegia 4	2020-05-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the SPAST gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with hereditary spastic paraplegia (PMID: 18701882, 25341883, 23833562). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001198064	SCV002766829	pathogenic	Hereditary spastic paraplegia 4	2022-03-31	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) 0211 - 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) 0703 - Other splice region variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.807+1G>A and c.870+3A>G have been observed in several individuals with spastic paraplegia and been classified as pathogenic by clinical laboratories in ClinVar (PMID: 25341883). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed in three individuals, once in a family with hereditary spastic paraplegia and twice classified as pathogenic by clinical laboratories in ClinVar (PMID: 18701882). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004697065	SCV005198329	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001198064	SCV005663656	pathogenic	Hereditary spastic paraplegia 4	2024-06-10	criteria provided, single submitter	clinical testing