rs142888296

Positions:

chr5-151886774-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The ENST00000274576.9(GLRA1):c.199G>A(p.Val67Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,612,940 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

GLRA1
ENST00000274576.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.39

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a topological_domain Extracellular (size 221) in uniprot entity GLRA1_HUMAN there are 23 pathogenic changes around while only 5 benign (82%) in ENST00000274576.9

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GLRA1	NM_000171.4 linkuse as main transcript	c.199G>A	p.Val67Met	missense_variant	3/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2 linkuse as main transcript	c.199G>A	p.Val67Met	missense_variant	3/9		NP_001139512.1
GLRA1	XM_047417105.1 linkuse as main transcript	c.247G>A	p.Val83Met	missense_variant	3/9		XP_047273061.1
GLRA1	NM_001292000.2 linkuse as main transcript	c.-51G>A		5_prime_UTR_variant	2/8		NP_001278929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.199G>A	p.Val67Met	missense_variant	3/9	1	NM_000171.4	ENSP00000274576	P4	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.199G>A	p.Val67Met	missense_variant	3/9	1		ENSP00000411593	A1	P23415-1
GLRA1	ENST00000471351.2 linkuse as main transcript	n.482G>A		non_coding_transcript_exon_variant	3/8	1
GLRA1	ENST00000462581.6 linkuse as main transcript	c.71G>A	p.Arg24His	missense_variant, NMD_transcript_variant	2/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251238

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000349

AC:

510

AN:

1460612

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

230

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000444

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000184

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary hyperekplexia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 67 of the GLRA1 protein (p.Val67Met). This variant is present in population databases (rs142888296, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of autosomal recessive hyperekplexia (PMID: 30182260; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 575744). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

GLRA1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2023

The GLRA1 c.199G>A variant is predicted to result in the amino acid substitution p.Val67Met. This variant was reported in the compound heterozygous state in an individual with hyperekplexia. The father who carried this variant was unaffected and the mother carrying the second GLRA1 variant (loss of function) was affected by hyperekplexia with a less severe phenotype, suggesting that p.Val67Met may act as a hypomorphic allele only enhancing the phenotype (Milenkovic et al. 2018. PubMed ID: 30182260). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-151266335-C-T). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2024

Reported in an individual with hyperekplexia who inherited the variant from their unaffected father and harbored an additional GLRA1 variant in trans; the additional variant was inherited from a similarly affected mother (PMID: 30182260); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30182260) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.84

MVP

0.90

MPC

2.1

ClinPred

0.69

GERP RS

5.5

Varity_R

0.85

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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