Submissions for variant NM_025137.4(SPG11):c.7132T>C (p.Phe2378Leu)

gnomAD frequency: 0.00009  dbSNP: rs150571352

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198221	SCV000255134	uncertain significance	Hereditary spastic paraplegia 11	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2378 of the SPG11 protein (p.Phe2378Leu). This variant is present in population databases (rs150571352, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SPG11-related conditions (PMID: 27066562). ClinVar contains an entry for this variant (Variation ID: 216774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV000609376	SCV000730587	likely benign	not specified	2018-02-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Baylor Genetics	RCV001331387	SCV001523420	uncertain significance	Amyotrophic lateral sclerosis type 5	2020-05-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847903	SCV002105777	uncertain significance	Hereditary spastic paraplegia	2020-01-14	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000198221	SCV002570395	uncertain significance	Hereditary spastic paraplegia 11	2022-07-11	criteria provided, single submitter	clinical testing	This SPG11 variant (rs150571352) is rare (<0.1%) in a large population dataset (gnomAD: 52/282406 total alleles; 0.02%; no homozygotes) and has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be damaging while another predicts that it would be tolerated. The phenylalanine residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 39 splicing, although this has not been confirmed experimentally to our knowledge. This variant was identified in a homozygous state in a single family with juvenile motor neuron disease. However, an additional homozygous nonsense variant in the SPG11 gene (c.2250delT) was also identified in affected family members making the functional impact of c.7132T>C alone unclear. Due to insufficient evidence, we consider the clinical significance of c.7132T>C to be uncertain at this time.
Ambry Genetics	RCV002363018	SCV002662286	uncertain significance	Inborn genetic diseases	2023-11-27	criteria provided, single submitter	clinical testing	The c.7132T>C (p.F2378L) alteration is located in exon 39 (coding exon 39) of the SPG11 gene. This alteration results from a T to C substitution at nucleotide position 7132, causing the phenylalanine (F) at amino acid position 2378 to be replaced by a leucine (L). The altered amino acid is well conserved throughout evolution:_x000D_ _x000D_ The p.F2378 amino acid is conserved in available primate species. The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.F2378L alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696869	SCV005198338	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252105	SCV001427854	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing