rs281864914

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate

The NM_000171.4(GLRA1):c.299G>A(p.Arg100His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.70

Variant links:

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000171.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-151859963-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2196359.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 5-151859962-C-T is Pathogenic according to our data. Variant chr5-151859962-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38328.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-151859962-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GLRA1	NM_000171.4 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	4/9	ENST00000274576.9
GLRA1	NM_001146040.2 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	4/9
GLRA1	NM_001292000.2 linkuse as main transcript	c.50G>A	p.Arg17His	missense_variant	3/8
GLRA1	XM_047417105.1 linkuse as main transcript	c.347G>A	p.Arg116His	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	4/9	1	NM_000171.4	P4	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	4/9	1		A1	P23415-1
GLRA1	ENST00000471351.2 linkuse as main transcript	n.582G>A		non_coding_transcript_exon_variant	4/8	1
GLRA1	ENST00000462581.6 linkuse as main transcript	c.*57G>A		3_prime_UTR_variant, NMD_transcript_variant	3/8	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251452

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727210

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hyperekplexia 1

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Oct 04, 2012

- -

Hereditary hyperekplexia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 17, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg100 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been observed in individuals with GLRA1-related conditions (PMID: 16078201, 24108130), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 25568133). 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 GLRA1 protein function. ClinVar contains an entry for this variant (Variation ID: 38328). This variant is also known as p.R72H. This missense change has been observed in individual(s) with autosomal recessive hyperekplexia (PMID: 16078201). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs281864914, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 100 of the GLRA1 protein (p.Arg100His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.38

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.7

H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.97

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.93

MPC

2.3

ClinPred

1.0

GERP RS

5.4

Varity_R

0.92

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over