rs779234204

chr5-151859870-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Extracellular (size 221) in uniprot entity GLRA1_HUMAN there are 20 pathogenic changes around while only 5 benign (80%) in NM_000171.4
• 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: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.391G>A	p.Glu131Lys	missense_variant	4/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.391G>A	p.Glu131Lys	missense_variant	4/9
GLRA1	NM_001292000.2	c.142G>A	p.Glu48Lys	missense_variant	3/8
GLRA1	XM_047417105.1	c.439G>A	p.Glu147Lys	missense_variant	4/9

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251486 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

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: 16 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727216

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.: 32

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary hyperekplexia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
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	D
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

Other links and lift over

dbSNP: rs779234204; hg19: chr5-151239431; COSMIC: COSV99199478;