Submissions for variant NM_001371279.1(REEP1):c.844G>A (p.Glu282Lys)

gnomAD frequency: 0.00041  dbSNP: rs189652973

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000415754	SCV000252191	benign	not provided	2020-10-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16826527)
Illumina Laboratory Services, Illumina	RCV000986787	SCV000432410	likely benign	Hereditary spastic paraplegia 31	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000415754	SCV000493298	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	REEP1: PP3, BS1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000986787	SCV001000638	likely benign	Hereditary spastic paraplegia 31	2023-08-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000986787	SCV001135911	uncertain significance	Hereditary spastic paraplegia 31	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165456	SCV003865421	likely benign	Inborn genetic diseases	2023-02-20	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000415754	SCV004562123	uncertain significance	not provided	2023-11-17	criteria provided, single submitter	clinical testing	The REEP1 c.*50G>A variant (rs189652973), also known as c.606+50G>A, is reported in the literature in an individual affected with spastic paraplegia with a family history of disease (Zuchner 2006). This variant was also observed in an unaffected relative of an affected individual, although no neurological examination information was provided (Zuchner 2006). The c.*50G>A variant is reported in ClinVar (Variation ID: 215087), and is observed in the non-Finnish European population with an allele frequency of 0.08% (101/126844 alleles) in the Genome Aggregation Database (v2.1.1). 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), however this was not verified with functional studies. Given the lack of clinical and functional data, the significance of the c.*50G>A variant is uncertain at this time. References: 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. PMID: 16826527.