rs1064792986

Variant names:

• chr2-86232666-GGCTGGCCGTGTTTGCC-G
• rs1064792986
• NM_001371279.1:c.538_553delGGCAAACACGGCCAGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001371279.1(REEP1):​c.538_553delGGCAAACACGGCCAGC​(p.Gly180LeufsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G180G) has been classified as Likely benign. 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
• Publications: 0 publications found

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]

REEP1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 31

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, type 5B

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spinal muscular atrophy, distal, autosomal recessive, 6

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 411806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.538_553delGGCAAACACGGCCAGC	p.Gly180LeufsTer32	frameshift_variant	Exon 6 of 9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7	c.538_553delGGCAAACACGGCCAGC	p.Gly180LeufsTer32	frameshift_variant	Exon 6 of 9	5	NM_001371279.1	ENSP00000438346.3

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

May 18, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. A similar deletion (c.537_540del) that causes a coding sequence extension, was reported in a family affected with hereditary spastic paraplegia (PMID: 18321925). At this time, experimental studies investigating the impact of this coding sequence extension on REEP1 protein function have not been reported. 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. -

not provided Pathogenic:1

Jun 09, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

Splicing

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

Other links and lift over

dbSNP: rs1064792986; hg19: chr2-86459789;