ClinVar Miner

Submissions for variant NM_001371279.1(REEP1):c.837G>T (p.Ser279=) (rs377637314)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200803 SCV000252187 uncertain significance not specified 2017-06-07 criteria provided, single submitter clinical testing The c.*43 G>T sequence change has been reported previously as c.606+43 G>T in several unrelated individuals with complicated and uncomplicated hereditary spastic paraplegia, however segregation analysis was not performed for these individuals (Züchner et al., 2006; Beetz et al., 2008; Schlang et al., 2008; Hewamadduma et al., 2009; Mishra et al., 2009; McCorquodale et al., 2011; Elert-Dobkowska et al., 2015). The c.*43 G>T variant is located in the 3' untranslated region (UTR) of the REEP1 gene at a position that is not conserved. This substitution disrupts a G:U wobble base pair, affecting the inhibitory effect on RNA-mediated repression of translation; therefore, the authors predict that the c.*43 G>T variant would lead to less available REEP1 protein, however in the absence of functional studies the actual affect of this variant is unknown (Züchner et al., 2006). The c.*43 G>T variant is observed in 83/66706 (0.12%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000001938 SCV000641180 benign Spastic paraplegia 31, autosomal dominant 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000001938 SCV001135912 uncertain significance Spastic paraplegia 31, autosomal dominant 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000200803 SCV001157494 uncertain significance not specified 2019-04-25 criteria provided, single submitter clinical testing The REEP1 c.*43G>T variant (rs377637314), also known as c.606+43G>T, is reported in the literature in multiple individuals affected with spastic paraplegia, many of whom also had a family history of disease (Beetz 2008, Elert-Dobkowska 2015, Hewamadduma 2009, Schlang 2008, Zuchner 2006). This variant has been observed in at least one unaffected relative of an affected individual, although no neurological examination of the unaffected individual was performed (Beetz 2008). The c.*43G>T variant is found in the non-Finnish European population with an overall allele frequency of 0.14% (180/126816 alleles) in the Genome Aggregation Database. This variant occurs in the 3' untranslated region at a nucleotide that is moderately conserved and is predicted to alter a microRNA binding site and impact protein levels (Zuchner 2006), although functional studies would be required to confirm this. In an alternative transcript, NM_001164732.1, this is a synonymous variant, but computational analyses (Alamut v.2.11) predict that it does not alter splicing. Given the lack of clinical and functional data, the significance of the c.*43G>T variant is uncertain at this time. References: Beetz C et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008 Apr;131(Pt 4):1078-86. Elert-Dobkowska E et al. Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. J Neurol Sci. 2015 Dec 15;359(1-2):35-9. Hewamadduma C et al. New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics. 2009 Apr;10(2):105-10. Schlang KJ et al. Autosomal dominant hereditary spastic paraplegia: novel mutations in the REEP1 gene (SPG31). BMC Med Genet. 2008 Jul 21;9:71. Zuchner S et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. 2006 Aug;79(2):365-9.
Illumina Clinical Services Laboratory,Illumina RCV000001938 SCV001297655 benign Spastic paraplegia 31, autosomal dominant 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
OMIM RCV000001938 SCV000022096 pathogenic Spastic paraplegia 31, autosomal dominant 2009-04-01 no assertion criteria provided literature only

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