rs281864921

Positions:

• chr5-151829058-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000171.4(GLRA1):​c.921del​(p.Tyr307Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.482

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-151829058-CA-C is Pathogenic according to our data. Variant chr5-151829058-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 38335.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.921del	p.Tyr307Ter	frameshift_variant	8/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.921del	p.Tyr307Ter	frameshift_variant	8/9
GLRA1	NM_001292000.2	c.672del	p.Tyr224Ter	frameshift_variant	7/8
GLRA1	XM_047417105.1	c.969del	p.Tyr323Ter	frameshift_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.921del	p.Tyr307Ter	frameshift_variant	8/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.921del	p.Tyr307Ter	frameshift_variant	8/9	1		A1
GLRA1	ENST00000462581.6	c.*679del		3_prime_UTR_variant, NMD_transcript_variant	7/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Oct 04, 2012

- -

Hereditary hyperekplexia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2018

This sequence change creates a premature translational stop signal (p.Tyr307*) in the GLRA1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GLRA1 are known to be pathogenic (PMID: 20631190). This variant has been observed to segregate with hyperekplexia in a family (PMID: 15771552). ClinVar contains an entry for this variant (Variation ID: 38335). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs281864921; hg19: chr5-151208619;