rs1064792986

Positions:

• chr2-86232666-GGCTGGCCGTGTTTGCC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001371279.1(REEP1):​c.538_553del​(p.Gly180LeufsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: REEP1 NM_001371279.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.31

Genes affected

REEP1 (HGNC:25786): (receptor accessory protein 1) This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-86232666-GGCTGGCCGTGTTTGCC-G is Pathogenic according to our data. Variant chr2-86232666-GGCTGGCCGTGTTTGCC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.538_553del	p.Gly180LeufsTer32	frameshift_variant	6/9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7	c.538_553del	p.Gly180LeufsTer32	frameshift_variant	6/9	5	NM_001371279.1	ENSP00000438346

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 31 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2016

In summary, this is a novel frameshift and extension with uncertain impact on protein function. A similar variant was reported in affected individuals, however, without additional genetic or functional evidence, this variant has been classified as Likely Pathogenic. At this time, experimental studies investigating the impact of this coding sequence extension on REEP1 protein function have not been reported. A similar deletion (c.537_540del) that causes a coding sequence extension, was reported in a family affected with hereditary spastic paraplegia (PMID: 18321925). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a REEP1-related disease. This sequence change deletes 16 nucleotides from exon 6 of the REEP1 mRNA (c.538_553del), causing a frameshift at codon 180. This creates a new translational stop signal in the last exon of the REEP1 mRNA and extends the coding sequence by 16 amino acids. (p.Gly180Leufs*38). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2017

A variant that is likely pathogenic has been identified in the REEP1 gene. The c.538_553del16 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.538_553del16 variant causes a frameshift starting with codon Glycine 180, changes this amino acid to a Leucine residue and creates a Stop codon at position 38 of the new reading frame, denoted p.Gly180LeufsX38. This variant is predicted to cause a protein extension as the last 22 amino acids are replaced with 37 incorrect amino acids. Furthermore, the c.538_553del16 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the c.538_553del16 variant has not been previously reported to our knowledge, other variants in the REEP1 gene that are predicted to cause a protein extension have been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064792986; hg19: chr2-86459789;