rs1554083597

chr5-151851509-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000171.4(GLRA1):c.793C>T(p.Leu265Phe) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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 Likely_pathogenic. Variant got 6 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, 4 uncertain in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.793C>T	p.Leu265Phe	missense_variant	7/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.793C>T	p.Leu265Phe	missense_variant	7/9
GLRA1	NM_001292000.2	c.544C>T	p.Leu182Phe	missense_variant	6/8
GLRA1	XM_047417105.1	c.841C>T	p.Leu281Phe	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.793C>T	p.Leu265Phe	missense_variant	7/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.793C>T	p.Leu265Phe	missense_variant	7/9	1		A1
GLRA1	ENST00000471351.2	n.1076C>T		non_coding_transcript_exon_variant	7/8	1
GLRA1	ENST00000462581.6	c.*551C>T		3_prime_UTR_variant, NMD_transcript_variant	6/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hyperekplexia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 532833). This variant has not been reported in the literature in individuals affected with GLRA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 265 of the GLRA1 protein (p.Leu265Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.89
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	D;B
Vest4		0.88
MutPred		0.75		Loss of catalytic residue at L265 (P = 0.0265);Loss of catalytic residue at L265 (P = 0.0265);
MVP		0.98
MPC		2.1
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.93

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: rs1554083597; hg19: chr5-151231070;