rs121918410

Variant names:

• chr5-151829060-T-C
• rs121918410
• NM_000171.4:c.920A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y307S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.79
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 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, 6 uncertain in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-151829060-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 38334.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.920A>G	p.Tyr307Cys	missense_variant	Exon 8 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.920A>G	p.Tyr307Cys	missense_variant	Exon 8 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.671A>G	p.Tyr224Cys	missense_variant	Exon 7 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.968A>G	p.Tyr323Cys	missense_variant	Exon 8 of 9		XP_047273061.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 1 Pathogenic:4

Jul 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 05, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

May 13, 2021

Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 21, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect by impairing the agonist-activated currents, decreasing glycine sensitivity, and lowering channel conductance (PMID: 9009272); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Y279C; This variant is associated with the following publications: (PMID: 7611730, 34015165, 9009272) -

Hereditary hyperekplexia Pathogenic:1

Nov 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.8
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918410; hg19: chr5-151208621;