rs779234204

Positions:

chr5-151859870-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000171.4(GLRA1):c.391G>A(p.Glu131Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,840 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: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

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

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 Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 5-151859870-C-T is Pathogenic according to our data. Variant chr5-151859870-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464187.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GLRA1	NM_000171.4 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	4/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	4/9		NP_001139512.1
GLRA1	NM_001292000.2 linkuse as main transcript	c.142G>A	p.Glu48Lys	missense_variant	3/8		NP_001278929.1
GLRA1	XM_047417105.1 linkuse as main transcript	c.439G>A	p.Glu147Lys	missense_variant	4/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	4/9	1	NM_000171.4	ENSP00000274576	P4	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.391G>A	p.Glu131Lys	missense_variant	4/9	1		ENSP00000411593	A1	P23415-1
GLRA1	ENST00000471351.2 linkuse as main transcript	n.674G>A		non_coding_transcript_exon_variant	4/8	1
GLRA1	ENST00000462581.6 linkuse as main transcript	c.*149G>A		3_prime_UTR_variant, NMD_transcript_variant	3/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251486

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000109

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

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:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

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 30, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 131 of the GLRA1 protein (p.Glu131Lys). This variant is present in population databases (rs779234204, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive hyperekplexia (PMID: 20631190; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Glu103Lys. ClinVar contains an entry for this variant (Variation ID: 464187). 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%. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 28174298). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2021

The c.391G>A (p.E131K) alteration is located in exon 4 (coding exon 4) of the GLRA1 gene. This alteration results from a G to A substitution at nucleotide position 391, causing the glutamic acid (E) at amino acid position 131 to be replaced by a lysine (K). Based on data from the Genome Aggregation Database (gnomAD) database, the GLRA1 c.391G>A alteration was observed in <0.01% (5/251486) of total alleles studied, with a frequency of 0.01% (4/34592) in the Latino subpopulation. This alteration was reported in trans with a frameshift alteration in a patient with hyperekplexia (Chung, 2010). This amino acid position is completely conserved on sequence alignment. In vitro studies have demonstrated altered channel function (Chung, 2010; Safar, 2017). The in silico prediction for the p.E131K alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.036

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.34

B;P

Vest4

0.97

MutPred

0.65

Gain of methylation at E131 (P = 0.0283);Gain of methylation at E131 (P = 0.0283);

MVP

0.86

MPC

2.1

ClinPred

0.94

GERP RS

5.5

Varity_R

0.96

gMVP

0.88

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