chr16-89553853-G-C
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_003119.4(SPG7):c.1996G>C(p.Gly666Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G666V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003119.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.1996G>C | p.Gly666Arg | missense_variant | 15/17 | ENST00000645818.2 | |
SPG7 | NM_001363850.1 | c.1996G>C | p.Gly666Arg | missense_variant | 15/18 | ||
SPG7 | XM_047434537.1 | c.1123G>C | p.Gly375Arg | missense_variant | 10/13 | ||
SPG7 | XM_047434540.1 | c.682G>C | p.Gly228Arg | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.1996G>C | p.Gly666Arg | missense_variant | 15/17 | NM_003119.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250942Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135866
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461164Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726900
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74386
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 25, 2022 | DNA sequence analysis of the SPG7 gene demonstrated a sequence change, c.1996G>C, in exon 15 that results in an amino acid change, p.Gly666Arg. The p.Gly666Arg change affects a highly conserved amino acid residue located in a domain of the SPG7 protein that is known to be functional. The p.Gly666Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in the literature in trans with a pathogenic variant in two individuals with spastic paraplegia (PMID: 23733235). This sequence change has been described in the gnomAD database with a frequency of 0.0008% in the overall population (dbSNP rs752989523). These collective evidences indicate that this sequence change is likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported previously, along with a second variant, in individuals with spastic paraplegia (Yoon et al., 2013).; This variant is associated with the following publications: (PMID: 23733235, 22571692) - |
Hereditary spastic paraplegia 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 666 of the SPG7 protein (p.Gly666Arg). This variant is present in population databases (rs752989523, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. 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 SPG7 protein function. ClinVar contains an entry for this variant (Variation ID: 216571). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23733235; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at