rs121918408

Positions:

• chr5-151851406-C-A
• chr5-151851406-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000274576.9(GLRA1):​c.896G>T​(p.Arg299Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R299Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 ENST00000274576.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.73

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000274576.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-151851406-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 5-151851406-C-A is Pathogenic according to our data. Variant chr5-151851406-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16060.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.896G>T	p.Arg299Leu	missense_variant	7/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.896G>T	p.Arg299Leu	missense_variant	7/9		NP_001139512.1
GLRA1	NM_001292000.2	c.647G>T	p.Arg216Leu	missense_variant	6/8		NP_001278929.1
GLRA1	XM_047417105.1	c.944G>T	p.Arg315Leu	missense_variant	7/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.896G>T	p.Arg299Leu	missense_variant	7/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.896G>T	p.Arg299Leu	missense_variant	7/9	1		ENSP00000411593	A1
GLRA1	ENST00000471351.2	n.1179G>T		non_coding_transcript_exon_variant	7/8	1
GLRA1	ENST00000462581.6	c.*654G>T		3_prime_UTR_variant, NMD_transcript_variant	6/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 22, 1994	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2024

Published functional studies demonstrate a damaging effect as R299L reduces agonist activity (PMID: 7925268, 7518444); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28122427, 7518444, 9009272, 7826634, 8298642, 7925268) -

Hereditary hyperekplexia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 299 of the GLRA1 protein (p.Arg299Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hyperekplexia (PMID: 8298642; Invitae). This variant is also known as p.Arg271Leu. ClinVar contains an entry for this variant (Variation ID: 16060). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLRA1 protein function. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 7518444). This variant disrupts the p.Arg299 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8298642, 8733061, 19073849, 28122427, 28138086). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.91
Sift	Benign	0.042	D;D
Sift4G	Benign	0.080	T;T
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.88		Loss of phosphorylation at S301 (P = 0.0564);Loss of phosphorylation at S301 (P = 0.0564);
MVP		0.94
MPC		2.1
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.81
gMVP		0.97

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: rs121918408; hg19: chr5-151230967;