ClinVar Genomic variation as it relates to human health

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiment showed impaired ATPase activity (PMID:20186691). 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. The variant is located in a region that is considered important for protein function and/or structure.

The c.1045G>A (p.G349S) alteration is located in exon 8 (coding exon 8) of the SPG7 gene. This alteration results from a G to A substitution at nucleotide position 1045, causing the glycine (G) at amino acid position 349 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD) database, the SPG7 c.1045G>A alteration was observed in 0.08% (232/281994) of total alleles studied, with a frequency of 0.16% (201/128548) in the European (non-Finnish) subpopulation. This alteration has been identified in the compound heterozygous state with various other SPG7 variants in multiple unrelated patients with spastic paraplegia and/or cerebellar ataxia (Bonn, 2010; Hewamadduma, 2018; Klebe, 2012; Kumar, 2013; Schlipf, 2011; van Gassen, 2012). This amino acid position is highly conserved in available vertebrate species. Functional studies in yeast showed that this alteration impairs enzyme activity (Bonn, 2010). The p.G349S alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The SPG7 c.1045G>A (p.Gly349Ser) missense variant is reported in 11 studies in which it is found in at least 25 patients with spastic paraplegia, including in 19 patients in a compound heterozygous state and in six patients in a heterozygous state (Brugman et al. 2008; Bonn et al. 2010; Schlipf et al. 2011; Klebe et al. 2012; Van Gassen et al. 2012; Kumar et al. 2013; Roxburgh et al. 2013; Yoon et al. 2013; Fogel et al. 2014; Marcotulli et al. 2014; Choquet et al. 2016). The p.Gly349Ser variant was reported in seven of 1104 control chromosomes, and is found at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The Gly349 residue is conserved across species. Functional studies in yeast demonstrated that the variant results in impaired enzyme activity (Bonn et al. 2010). Based on the evidence, the p.Gly349Ser variant is classified as pathogenic for autosomal recessive spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The c.1045G>A;p.(Gly349Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 6819; PMID: 27790088;27016405; 26626314; 25133958; 25034272; 23812641; 23733235) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 20186691) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (AAA domain) - PM1. The p.(Gly349Ser) was detected in trans with a pathogenic variant (PMID: 26626314; 25034272; 23733235; 20186691) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 25133958 ; 20186691) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Variant summary: SPG7 c.1045G>A (p.Gly349Ser) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 0.00083 in 250588 control chromosomes (gnomAD). c.1045G>A has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example: Schlipf_2011, Bonn_2010, vanGassen_2012, Roxburgh_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant disrupts normal protein function (Bonn_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20186691, 23269439, 21623769, 22964162). Nineteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified this variant pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 349 of the SPG7 protein (p.Gly349Ser). This variant is present in population databases (rs141659620, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 18799786, 20186691, 21623769, 22964162, 23065789, 23269439, 23733235, 23812641, 25034272, 25133958, 26626314, 27016405). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6819). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPG7 function (PMID: 20186691). For these reasons, this variant has been classified as Pathogenic.

The SPG7 c.1045G>A; p.Gly349Ser variant (rs141659620) is reported in the literature in numerous compound heterozygous individuals affected with hereditary spastic paraplegia (Bonn 2010, Brugman 2008, Hewamadduma 2018, Mahoney 2020, Rizzo 2020). This variant is found in the non-Finnish European population with an allele frequency of 0.16% (201/128,548 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.948). Consistent with these predictions, functional analysis of this variant in a heterologous yeast assay suggests it fails to complement yeast similar to wildtype SPG7 (Bonn 2010). Based on available information, this variant is considered to be pathogenic. References: Bonn F et al. Functional evaluation of paraplegin mutations by a yeast complementation assay. Hum Mutat. 2010 May;31(5):617-21. PMID: 20186691. Brugman F et al. Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes. Neurology. 2008 Nov 4;71(19):1500-5. PMID: 18799786. Hewamadduma CA et al. Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations. Neurol Genet. 2018 Oct 24;4(6):e279. PMID: 30533525. Mahoney CJ et al. A novel phenotype of hereditary spastic paraplegia type 7 associated with a compound heterozygous mutation in paraplegin. Muscle Nerve. 2020 Jul;62(1):E44-E45. PMID: 32270516. Rizzo G et al. ''Eye of tiger sign" mimic in patients with spastic paraplegia gene 7 (SPG7) mutations. Parkinsonism Relat Disord. 2020 Dec;81:158-160. PMID: 33157434.

This sequence change is predicted to replace glycine with serine at codon 349 of the SPG7 protein (p.Gly349Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and located in the AAA ATPase domain (PMID: 19841671). There is a small physicochemical difference between glycine and serine. The variant is present in a large population cohort at a frequency of 0.08% (rs141659620, 232/281,994 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in multiple individuals with a second pathogenic allele with phenotypes including pure/complex hereditary spastic paraplegia and spastic ataxia, and segregates with disease in at least two families (PM3_VeryStrong, PP1_Moderate; PMID: 20186691, 21623769, 23812641, 26626314, 30533525). Additionally, the missense change impairs proteolytic activity in a in vitro yeast complementation assay (PS3_Supporting; PMID: 20186691). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Moderate, PS3_Supporting, PP3.

PS3, PS4, PM2, PM3_strong, PP3

Reported as heterozygous in an individual with HSP in whom a second variant was not described (PMID: 18799786); Functional studies performed in yeast cells found that G349S perturbs the function of the SPG7 protein (PMID: 20186691); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27016405, 29431110, 32816195, 34662886, 34758253, 23065789, 23269439, 21623769, 23733235, 25133958, 26626314, 25034272, 23812641, 30747022, 32447552, 31980526, 32270516, 31589614, 33300680, 33157434, 33841295, 34531397, 30533525, 27790088, 22964162, 20186691, 18799786, 22571692, 34983064, 36781956)

SPG7: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO#0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (232 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (p.(Gly349Arg): 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 a binding site within the AAA domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been classified as likely pathogenic or pathogenic by multiple diagnostic laboratories and has been reported in multiple individuals with spastic paraplegia 7 (ClinVar, PMIDs: 30533525, 35959404). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies in mAAA protease-deficient yeast cells transfected with mutant human paraplegin, displayed impaired proteolytic enzyme activity (PMID: 20186691). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_003119.3(SPG7):c.1529C>T; p.(Ala510Val)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The SPG7 c.1045G>A variant is predicted to result in the amino acid substitution p.Gly349Ser. This variant has been reported in the compound heterozygous state to be causative for autosomal recessive spastic paraplegia (Bonn et al. 2010. PubMed ID: 20186691; Schlipf et al. 2011. PubMed ID: 21623769; Klebe et al. 2012. PubMed ID: 23065789; Roxburgh et al. 2012. PubMed ID: 23269439; van Gassen et al. 2012. PubMed ID: 22964162; Choquet et al. 2015. PubMed ID: 26626314). It has also been reported in the heterozygous state alone in at least two patients affected with spastic paraplegia; however, other individuals who harbored this variant in the heterozygous state alone were asymptomatic (Brugman et al. 2008. PubMed ID: 18799786; Fogel et al. 2014. PubMed ID: 25133958; Bonn et al. 2010. PubMed ID: 20186691; Schlipf et al. 2011. PubMed ID: 21623769). Functional studies have shown that the p.Gly349Ser results in impaired enzyme activity in yeast cells (Bonn et al. 2010. PubMed ID: 20186691). This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be responsible for an early-onset, autosomal dominant form of disease. Taken together, this variant is classified as pathogenic.