Submissions for variant NM_025137.4(SPG11):c.130C>T (p.Arg44Trp)

gnomAD frequency: 0.00001  dbSNP: rs1304995096

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001345981	SCV001540138	uncertain significance	Hereditary spastic paraplegia 11	2022-05-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 44 of the SPG11 protein (p.Arg44Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1042082). 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: "Deleterious"; PolyPhen-2: "Benign"; 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847247	SCV002105657	uncertain significance	Hereditary spastic paraplegia	2018-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002468234	SCV002762929	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002468235	SCV002762930	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001345981	SCV002762931	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800983	SCV005422153	uncertain significance	not specified	2024-10-24	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.130C>T (p.Arg44Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-06 in 206932 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.130C>T in individuals affected with Hereditary Spastic Paraplegia, Type 11 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1042082). Based on the evidence outlined above, the variant was classified as uncertain significance.