Submissions for variant NM_014946.4(SPAST):c.1496G>A (p.Arg499His)

dbSNP: rs878854991

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230990	SCV000290034	pathogenic	Hereditary spastic paraplegia 4	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the SPAST protein (p.Arg499His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia 4 (PMID: 16009769, 16055926, 16682546, 18701882, 20562464). ClinVar contains an entry for this variant (Variation ID: 240950). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg499 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15095758, 15716377). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000230990	SCV000680389	pathogenic	Hereditary spastic paraplegia 4	2020-08-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623007	SCV000741401	likely pathogenic	Inborn genetic diseases	2016-03-17	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000230990	SCV000743204	pathogenic	Hereditary spastic paraplegia 4	2017-07-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000230990	SCV000745629	pathogenic	Hereditary spastic paraplegia 4	2016-10-14	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000713467	SCV000844078	pathogenic	not provided	2017-02-21	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000230990	SCV000898159	pathogenic	Hereditary spastic paraplegia 4	2018-08-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000230990	SCV000992839	pathogenic	Hereditary spastic paraplegia 4	2017-12-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000230990	SCV001135658	pathogenic	Hereditary spastic paraplegia 4	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000230990	SCV001429163	pathogenic	Hereditary spastic paraplegia 4	2016-06-17	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
National Institute of Neuroscience, National Center of Neurology and Psychiatry	RCV000230990	SCV001438322	pathogenic	Hereditary spastic paraplegia 4		criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000713467	SCV001446399	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000230990	SCV001450999	pathogenic	Hereditary spastic paraplegia 4		criteria provided, single submitter	clinical testing
Neurogenetics Laboratory, Gh Pitie Salpetriere Aphp	RCV000230990	SCV001481803	likely pathogenic	Hereditary spastic paraplegia 4		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000713467	SCV001715442	pathogenic	not provided	2019-05-12	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PM6, PP1
GeneDx	RCV000713467	SCV001751731	pathogenic	not provided	2022-07-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27260292, 16009769, 29761117, 29421991, 29980238, 30564185, 31486053, 31157359, 31227335, 30476002, 31216405, 31698101, 31031587, 33098801, 33624935)
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814125	SCV001755260	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
3billion	RCV000230990	SCV002058176	pathogenic	Hereditary spastic paraplegia 4	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29421991, 27260292, 16009769, 16055926, PS4_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29421991, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005660,VCV000801664, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.986, 3CNET: 0.998, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000230990	SCV002059652	pathogenic	Hereditary spastic paraplegia 4	2021-09-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847990	SCV002105613	pathogenic	Hereditary spastic paraplegia	2020-12-16	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000230990	SCV002766730	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 associated with 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 is mostly age-dependant penetrance 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 arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in individuals with spastic paraplegia, often occured de novo and has highly variable expressivity (ClinVar, DECIPHER, PMID: 34753439). (SP) 0600 - Variant is located in the annotated AAA domain (DECIPHER). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000230990	SCV003808093	pathogenic	Hereditary spastic paraplegia 4	2022-08-17	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP3 supporting
PreventionGenetics, part of Exact Sciences	RCV003422150	SCV004116580	pathogenic	SPAST-related disorder	2023-03-10	criteria provided, single submitter	clinical testing	The SPAST c.1496G>A variant is predicted to result in the amino acid substitution p.Arg499His. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has been reported in multiple patients with autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926; Shoukier et al. 2009. PubMed ID: 18701882; de Bot et al. 2010. PubMed ID: 20562464; Kim et al. 2014. PubMed ID: 25045380; Polymeris et al. 2016. PubMed ID: 27260292). A different substitution affecting the same amino acid residue (p.Arg499Cys) has also been reported to be pathogenic for autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926, Hazan et al. 1999. PubMed ID: 10610178; Evans et al. 2005. PubMed ID: 15716377; Shoukier et al. 2009. PubMed ID: 18701882). Taken together, we interpret the c.1496G>A (p.Arg499His) variant as pathogenic.
Eurofins Ntd Llc (ga)	RCV000713467	SCV000339060	uncertain significance	not provided	2016-01-29	flagged submission	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000230990	SCV001133115	pathogenic	Hereditary spastic paraplegia 4	2019-09-26	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000713467	SCV001958181	pathogenic	not provided		no assertion criteria provided	clinical testing
Human Genetics, University of Luebeck	RCV000230990	SCV003834786	pathogenic	Hereditary spastic paraplegia 4	2022-12-01	no assertion criteria provided	clinical testing