Submissions for variant NM_014946.4(SPAST):c.1196C>T (p.Ser399Leu)

dbSNP: rs1553317025

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516537	SCV000615382	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. The variant is located in a region that is considered important for protein function and/or structure.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686298	SCV000813810	pathogenic	Hereditary spastic paraplegia 4	2024-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 399 of the SPAST protein (p.Ser399Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11843700, 16832076, 18701882, 19875132, 22960362, 24824479, 25045380, 27334366, 29934652, 29980238). ClinVar contains an entry for this variant (Variation ID: 448442). Invitae Evidence 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 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 SPAST protein function. For these reasons, this variant has been classified as Pathogenic.
Paris Brain Institute, Inserm - ICM	RCV000686298	SCV001450956	pathogenic	Hereditary spastic paraplegia 4		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000516537	SCV001713172	likely pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000686298	SCV002768024	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-dependent 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) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) (AAA cassette, PMID: 29980238). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.Ser399Trp) has been reported as a VUS (ClinVar). (I) 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, LOVD, PMID: 29980238, PMID: 31594988, PMID: 25045380; PMID: 24824479). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000686298	SCV002811662	likely pathogenic	Hereditary spastic paraplegia 4	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000516537	SCV003803530	likely pathogenic	not provided	2024-04-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11843700, 24824479, 16832076, 18701882, 22960362, 19875132, 31594988, 30476002, 35487127, 29980238, 23252998, 31227335, 32619247, 21139634, 26094131)
CeGaT Center for Human Genetics Tuebingen	RCV000516537	SCV005434026	likely pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	SPAST: PM1, PM2, PS4:Moderate, PP2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000686298	SCV005438233	likely pathogenic	Hereditary spastic paraplegia 4	2024-12-20	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000516537	SCV001742312	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000516537	SCV002035258	likely pathogenic	not provided		no assertion criteria provided	clinical testing