Submissions for variant NM_025137.4(SPG11):c.5121G>T (p.Glu1707Asp)

gnomAD frequency: 0.00103  dbSNP: rs145643238

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456956	SCV000545193	uncertain significance	Hereditary spastic paraplegia 11	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1707 of the SPG11 protein (p.Glu1707Asp). This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon. This variant is present in population databases (rs145643238, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 406519). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000658710	SCV000780496	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000456956	SCV001279295	uncertain significance	Hereditary spastic paraplegia 11	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000658710	SCV001713701	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	PP3
GeneDx	RCV000658710	SCV001872959	uncertain significance	not provided	2024-12-06	criteria provided, single submitter	clinical testing	Reported previously in an individual with Parkinson disease; however, familial segregation information, in vitro functional studies, and additional clinical information were not included (PMID: 25174650); Reported previously in a patient with blindness; however, no further clinical information was provided and it is unclear if a second variant was present (PMID: 32483926); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 32171587, 25174650, Kalia2023[preprint], 32483926)
Ambry Genetics	RCV002339138	SCV002642237	uncertain significance	Inborn genetic diseases	2022-12-08	criteria provided, single submitter	clinical testing	The c.5121G>T variant (also known as p.E1707D), located in coding exon 29 of the SPG11 gene, results from a G to T substitution at nucleotide position 5121. The glutamic acid at codon 1707 is replaced by aspartic acid, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 29, which makes it likely to have some effect on normal mRNA splicing. The p.E1707D alteration was reported once in a cohort of 192 adult patients with neurodegenerative disorders in a patient with Parkinson's disease who also had a second alteration in the SPG11 gene, although phase of the alterations (cis vs. trans) was not determined (Ghani M, et al. Neurobiol Aging, 2015 Jan;36:545.e9-15). This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is unavailable. In addition, as a missense substitution, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002467808	SCV002763855	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467809	SCV002763856	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000456956	SCV002763857	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488606	SCV004241168	likely benign	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.5121G>T (p.Glu1707Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon.Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the 5' canonical splicing donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00076 in 1559200 control chromosomes, predominantly at a frequency of 0.0019 within the Latino subpopulation in the gnomAD database, including 1 homozygotes (genomAD, v4). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.5121G>T has been reported in the literature in individuals affected with Parkinsons disease or blindness, without strong evidence for causality (example, Dineiro_2020, Ghani_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia, Type 11. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32483926, 25174650). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000658710	SCV005193762	uncertain significance	not provided		criteria provided, single submitter	not provided
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252107	SCV001427856	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000658710	SCV001741844	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000658710	SCV001807827	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000658710	SCV001920320	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000658710	SCV001930882	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000658710	SCV001959698	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483617	SCV004228622	not provided	Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-03-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004748768	SCV005352239	uncertain significance	SPG11-related disorder	2024-09-07	no assertion criteria provided	clinical testing	The SPG11 c.5121G>T variant is predicted to result in the amino acid substitution p.Glu1707Asp. This variant resides at the exon/intron boundary and is predicted to alter splicing based on prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant was reported in an individual with Parkinson disease (Table S2, Ghani et al. 2015. PubMed ID: 25174650) and in a large cohort of patients with inherited retinal and optical nerve disorders (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.