ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.1045G>A (p.Gly349Ser) (rs141659620)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000198037 SCV000844090 pathogenic not provided 2016-04-15 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000007221 SCV000733557 pathogenic Spastic paraplegia 7 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000198037 SCV000855030 likely pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000007221 SCV000894098 pathogenic Spastic paraplegia 7 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000198037 SCV000252337 pathogenic not provided 2017-10-18 criteria provided, single submitter clinical testing The G349S variant in the SPG7 gene has been reported previously in association with spastic paraplegia in individuals who are compound heterozygotes for G349S and a second SPG7 variant (Bonn et al., 2010; Schlipf et al., 2011). Functional studies performed in yeast cells found that G349S perturbs the function of the SPG7 protein (Bonn et al., 2010). The NHLBI Exome Sequencing Project reports G349S was observed in 15/8600 (0.2%) alleles from individuals of European American background, although this variant was not present in the homozygous state. The G349S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (G354A) has been reported in association with spastic paraplegia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret G349S to be a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000007221 SCV000597234 likely pathogenic Spastic paraplegia 7 2015-09-02 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000007221 SCV000743901 pathogenic Spastic paraplegia 7 2016-04-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000007221 SCV000399749 pathogenic Spastic paraplegia 7 2017-04-27 criteria provided, single submitter clinical testing 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.
Invitae RCV000007221 SCV000640067 pathogenic Spastic paraplegia 7 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 349 of the SPG7 protein (p.Gly349Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs141659620, ExAC 0.1%). This variant has been reported in the compound heterozygous state or heterozygous state in many individuals affected with hereditary spastic paraplegia (PMID: 22964162, 18799786, 25133958, 23269439, 23733235, 23812641, 21623769, 27016405, 26626314, 25034272, 23065789) and has been shown to segregate with disease in two families (PMID: 20186691, 26626314). It has also been reported in the heterozygous state in an individual affected with sporadic amyotrophic lateral sclerosis (PMID: 27790088). ClinVar contains an entry for this variant (Variation ID: 6819). Experimental studies have shown that this missense change impairs enzyme activity in a yeast study (PMID: 20186691). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000007221 SCV000223951 pathogenic Spastic paraplegia 7 2014-10-20 criteria provided, single submitter clinical testing
Neurogenetics of motion laboratory,Montreal Neurological Institute RCV000007221 SCV000245723 pathogenic Spastic paraplegia 7 criteria provided, single submitter case-control
OMIM RCV000007221 SCV000027417 pathogenic Spastic paraplegia 7 2010-05-01 no assertion criteria provided literature only

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