chr15-44567553-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_025137.4(SPG11):c.6625C>T(p.Arg2209Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_025137.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SPG11 | NM_025137.4 | c.6625C>T | p.Arg2209Cys | missense_variant | Exon 36 of 40 | ENST00000261866.12 | NP_079413.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152070Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000227 AC: 57AN: 251434Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135892
GnomAD4 exome AF: 0.000324 AC: 474AN: 1461832Hom.: 0 Cov.: 34 AF XY: 0.000323 AC XY: 235AN XY: 727226
GnomAD4 genome AF: 0.000256 AC: 39AN: 152070Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20AN XY: 74272
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Uncertain:3
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2209 of the SPG11 protein (p.Arg2209Cys). This variant is present in population databases (rs374057859, gnomAD 0.05%). 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: 466559). 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 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. -
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with amyotrophic lateral sclerosis 5, juvenile (MIM#602099), Charcot-Marie-Tooth disease, axonal, type 2X (MIM#616668) and spastic paraplegia 11 (MIM#604360). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 62 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Spatacsin C-terminus domain (NCBI conserved domain). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.Arg2209His missense variant has been submitted as a variant of uncertain significance in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant is classified as a variant of uncertain significance in ClinVar. It has also been identified in one individual with amyotrophic lateral sclerosis however, the zygosity of this variant was not specified (ClinVar; PMID: 25299611). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Uncertain:2
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not specified Uncertain:1
Variant summary: SPG11 c.6625C>T (p.Arg2209Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR028107) of 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 0.00032 (i.e. in 513 carriers) in 1,606,906 control chromosomes (gnomAD v4). This frequency is not higher than the estimated maximum expected for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (0.0011), allowing no conclusion about variant significance. The variant c.6625C>T has been reported in the literature in individuals affected with amyotrophic lateral sclerosis (e.g. Couthouis_2014, Lamp_2018, Lattante_2020), however no second variant was specified in these cases. These reports therefore do not provide unequivocal conclusions about the role of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 466559). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The p.R2209C variant (also known as c.6625C>T), located in coding exon 36 of the SPG11 gene, results from a C to T substitution at nucleotide position 6625. The arginine at codon 2209 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Uncertain:1
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Hereditary spastic paraplegia Uncertain:1
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Amyotrophic lateral sclerosis type 5 Uncertain:1
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Charcot-Marie-Tooth disease axonal type 2X Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at