Submissions for variant NM_025137.4(SPG11):c.979C>G (p.Leu327Val)

gnomAD frequency: 0.00016  dbSNP: rs146109825

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000259263	SCV000337505	uncertain significance	not provided	2017-08-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811912	SCV000952203	uncertain significance	Hereditary spastic paraplegia 11	2022-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 327 of the SPG11 protein (p.Leu327Val). This variant is present in population databases (rs146109825, gnomAD 0.02%). 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: 284761). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPG11 protein function. 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.
Ambry Genetics	RCV002379128	SCV002694963	uncertain significance	Inborn genetic diseases	2023-04-25	criteria provided, single submitter	clinical testing	The c.979C>G (p.L327V) alteration is located in exon 5 (coding exon 5) of the SPG11 gene. This alteration results from a C to G substitution at nucleotide position 979, causing the leucine (L) at amino acid position 327 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002467715	SCV002764188	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467716	SCV002764189	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000811912	SCV002764190	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000259263	SCV004136531	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	SPG11: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586659	SCV005077425	uncertain significance	not specified	2024-04-05	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.979C>G (p.Leu327Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251416 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (9.5e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.979C>G 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: 284761). Based on the evidence outlined above, the variant was classified as uncertain significance.