rs121918263

chr2-86252037-G-A

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.337C>T(p.Arg113Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: REEP1 NM_001371279.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.07

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 2-86252037-G-A is Pathogenic according to our data. Variant chr2-86252037-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-86252037-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP1	NM_001371279.1	c.337C>T	p.Arg113Ter	stop_gained	5/9	ENST00000538924.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP1	ENST00000538924.7	c.337C>T	p.Arg113Ter	stop_gained	5/9	5	NM_001371279.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 31 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 13, 2012	- -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in REEP1 are known to be pathogenic (PMID: 24098485). This variant has been observed in an individual affected with hereditary spastic paraplegia (PMID: 23400676) and to segregates with autosomal dominant hereditary spastic paraplegia in several families (PMID: 19034539, 29629531). ClinVar contains an entry for this variant (Variation ID: 1863). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg113*) in the REEP1 gene. It is expected to result in an absent or disrupted protein product. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22703882, 21618648, 24221643, 25525159, 19034539, 30637453, 23400676, 28003645, 27549087, 24098485, 12634509, 29629531, 33866115, 35297556, 35132160, 31913854, 20200447) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.96
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918263; hg19: chr2-86479160; COSMIC: COSV51256972;