2-86282216-G-T

Position:

• chr2-86282216-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001371279.1(REEP1):​c.59C>A​(p.Ala20Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A20A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: REEP1 NM_001371279.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.97

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 2-86282216-G-T is Pathogenic according to our data. Variant chr2-86282216-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-86282216-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.59C>A	p.Ala20Glu	missense_variant	2/9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7	c.59C>A	p.Ala20Glu	missense_variant	2/9	5	NM_001371279.1	ENSP00000438346.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456730 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725080

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 12, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair protein localization in the endoplasmic reticulum (PMID 24478229). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	REEP1: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2024	Published functional studies demonstrate that A20E increases neurite degeneration and affects neurite growth (PMID: 26201691); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24478229, 25525159, 18321925, 20718791, 16826527, 21618648, 32581362, 37147312, 33210134, 26201691, 22703882, 23812641) -

Hereditary spastic paraplegia 31 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 20 of the REEP1 protein (p.Ala20Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (HSP) (PMID: 16826527, 18321925, 20718791, 23812641). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1862). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt REEP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects REEP1 function (PMID: 22703882, 24478229, 26201691). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2015	- -

Spastic paraplegia Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;.;.;.;.;H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;.;.;.;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0010	D;.;.;.;.;D;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.97
MutPred		0.92		Gain of disorder (P = 0.1176);.;.;Gain of disorder (P = 0.1176);.;Gain of disorder (P = 0.1176);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918262; hg19: chr2-86509339;