ClinVar Genomic variation as it relates to human health

The p.Gly352ArgfsX44 (NM_003119.2 c.1053dup) (also referred to as c.1053_1054ins C or c.1047insC in the literature) variant in SPG7 has been reported in 7 compou nd heterozygous and 2 homozygous individuals with clinical diagnosis of heredita ry spastic paraplegia or ataxia, and segregated in two affected homozygous sibli ngs in one family (Tzoulis 2008, Klebe 2012, van Gassen 2012, Yoon 2013, Pfeffer 2015, Rydning 2016). This variant has also been reported in ClinVar (Variation ID#411675) as pathogenic by one laboratory. It has been identified in 23/125,780 European chromosomes by the Genome Aggregation Database (http://gnomad.broadins titute.org; rs760818649). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 352 and leads to a premature termination codon 44 amino acids downstream. This alteration is the n predicted to lead to a truncated or absent protein. Biallelic loss of function of the SPG7 gene has been associated with hereditary spastic paraplegia. In sum mary, the p.Gly352ArgfsX44 variant meets criteria to be classified as pathogenic for hereditary spastic paraplegia in an autosomal recessive manner based on its biallelic occurrence in individuals with this disease and its predicted null ef fect.

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32816195, 34758253, 27957547, 23733235, 25681447, 28444220, 30609409, 31589614, 18563470, 25976027)

This sequence change creates a premature translational stop signal (p.Gly352Argfs*44) in the SPG7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162). This variant is present in population databases (rs760818649, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (HSP) (PMID: 18563470, 21623769, 23065789, 23733235, 24727571, 25681447). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411675). For these reasons, this variant has been classified as Pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000411675 / PMID: 18563470 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

The SPG7 c.1053dupC variant is predicted to result in a frameshift and premature protein termination (p.Gly352Argfs*44). This variant has been reported in the homozygous and compound heterozygous state in patients with autosomal recessive hereditary spastic paraplegia (e.g., Tzoulis et al. 2008. PubMed ID: 18563470, designated 1047insC; Pfeffer et al. 2015. PubMed ID: 25681447). This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89598370-G-GC). Frameshift variants in SPG7 are expected to be pathogenic. This variant is interpreted as pathogenic.

This sequence change in SPG7 is a frameshift variant predicted to cause a premature stop codon, p.(Gly352Argfs*44), in biologically relevant exon 8/17, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID 20301286). The highest population minor allele frequency in the population database gnomAD v3.1 is 0.051% (21/41,458 alleles) in the African/African American population, which is consistent with recessive hereditary spastic paraplegia (HSP). This variant has been detected in at least nine individuals with HSP and/or spastic ataxia. Of those individuals, six were compound heterozygous for the variant and the same pathogenic missense variant (c.1529C>T, p.Ala510Val) (PMID: 25976027, 24727571, 23065789, 25681447, 27957547, 28444220). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PM2_Supporting.

SPG7: PVS1, PM2, PM3

Variant confirmed as disease-causing by referring clinical team