Submissions for variant NM_014946.4(SPAST):c.1216A>G (p.Ile406Val)

dbSNP: rs587777757

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497406	SCV000589637	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Identified in patients with HSP in published literature, but segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members (PMID: 16682546, 19423133, 20562464); Published functional studies demonstrate damaging effects, including aberrant in-frame splicing, destabilization of mutated transcript, and deficient in microtubule-severing activity (PMID: 16476945); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30476002, 16832076, 20562464, 19423133, 16476945, 31157359, 16055926, 34758253, 21139634, 26094131, 31594988, 34983064, 16682546)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006029	SCV001388127	pathogenic	Hereditary spastic paraplegia 4	2024-06-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 406 of the SPAST protein (p.Ile406Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia and was observed to be de novo in at least one individual (PMID: 16476945, 16682546, 16832076, 17971434, 18701882, 19423133). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5675). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SPAST protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Paris Brain Institute, Inserm - ICM	RCV000006029	SCV001450959	pathogenic	Hereditary spastic paraplegia 4		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000497406	SCV001880483	pathogenic	not provided	2020-12-16	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in one individual with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant resulted in a 30-bp deletion when expressed in a cell line. However, only 20% of transcript was affected and it is unclear if this is sufficient aberrant transcript to cause disease (PMID 16476945). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847589	SCV002105588	pathogenic	Hereditary spastic paraplegia	2017-08-15	criteria provided, single submitter	clinical testing
OMIM	RCV000006029	SCV000026211	pathogenic	Hereditary spastic paraplegia 4	2006-02-14	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV000006029	SCV001760086	likely pathogenic	Hereditary spastic paraplegia 4		no assertion criteria provided	clinical testing