Submissions for variant NM_025137.4(SPG11):c.2318T>G (p.Val773Gly)

gnomAD frequency: 0.00014  dbSNP: rs182080501

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193023	SCV000249014	uncertain significance	not specified	2015-01-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463915	SCV000545211	uncertain significance	Hereditary spastic paraplegia 11	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 773 of the SPG11 protein (p.Val773Gly). This variant is present in population databases (rs182080501, gnomAD 0.02%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 33589474). ClinVar contains an entry for this variant (Variation ID: 212292). 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. 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.
Athena Diagnostics	RCV001287994	SCV001474769	uncertain significance	not provided	2020-02-13	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847875	SCV002105683	uncertain significance	Hereditary spastic paraplegia	2019-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001287994	SCV002522026	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state as a variant of uncertain significance in an individual with ALS; segregation not performed (Shepheard et al., 2021); 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: 33589474)
Ambry Genetics	RCV002444782	SCV002734395	uncertain significance	Inborn genetic diseases	2023-04-11	criteria provided, single submitter	clinical testing	The c.2318T>G (p.V773G) alteration is located in exon 13 (coding exon 13) of the SPG11 gene. This alteration results from a T to G substitution at nucleotide position 2318, causing the valine (V) at amino acid position 773 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002467657	SCV002764067	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467658	SCV002764068	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000463915	SCV002764069	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000463915	SCV002767595	uncertain significance	Hereditary spastic paraplegia 11	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_025137.3(SPG11):c.2318T>G, has been identified in exon 12 of 40 of the SPG11 gene. The variant is predicted to result in a major amino acid change from valine to glycine at position 773 of the protein (NP_079413.3(SPG11):p.(Val773Gly)). The valine residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.01% (34 heterozygotes, 0 homozygotes). The variant has been previously described as a variant of certain significant (ClinVar, MSeqDR database). A different variant in the same codon resulting in a change to leucine has also been reported as a vaiant of uncertain significance (ClinVar, MSeqDR database). Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001287994	SCV001808458	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001287994	SCV001922255	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001287994	SCV001972768	uncertain significance	not provided		no assertion criteria provided	clinical testing