rs121918410

Positions:

• chr5-151829060-T-C
• chr5-151829060-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000171.4(GLRA1):​c.920A>G​(p.Tyr307Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.79

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Extracellular (size 10) in uniprot entity GLRA1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 5-151829060-T-C is Pathogenic according to our data. Variant chr5-151829060-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 16063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.920A>G	p.Tyr307Cys	missense_variant	8/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.920A>G	p.Tyr307Cys	missense_variant	8/9		NP_001139512.1
GLRA1	NM_001292000.2	c.671A>G	p.Tyr224Cys	missense_variant	7/8		NP_001278929.1
GLRA1	XM_047417105.1	c.968A>G	p.Tyr323Cys	missense_variant	8/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.920A>G	p.Tyr307Cys	missense_variant	8/9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.920A>G	p.Tyr307Cys	missense_variant	8/9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*678A>G		non_coding_transcript_exon_variant	7/8	1		ENSP00000430595.1
GLRA1	ENST00000462581.6	n.*678A>G		3_prime_UTR_variant	7/8	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 05, 2021	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	May 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1995	- -

Hereditary hyperekplexia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 307 of the GLRA1 protein (p.Tyr307Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hyperekplexia (PMID: 7611730, 11389164; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16063). 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: 9009272). This variant disrupts the p.Tyr307 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been observed in individuals with GLRA1-related conditions (PMID: 16236274), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.99
MutPred		0.92		Loss of catalytic residue at Y307 (P = 0.0674);Loss of catalytic residue at Y307 (P = 0.0674);
MVP		0.95
MPC		0.36
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.98

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: rs121918410; hg19: chr5-151208621;