ClinVar Genomic variation as it relates to human health

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.

REEP1: BP4, BP7

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.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

This variant is associated with the following publications: (PMID: 19034539, 18644145, 26671083, 20718791, 18321925, 19290790, 16826527)

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).