chr5-151829058-CA-C

Variant names:

• chr5-151829058-CA-C
• rs281864921
• NM_000171.4:c.921delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000171.4(GLRA1):​c.921delT​(p.Tyr307fs) 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 (★). Variant results in nonsense mediated mRNA decay.

• 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
• Publications: 1 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 38335.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000171.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	NM_000171.4	MANE Select	c.921delT	p.Tyr307fs	frameshift	Exon 8 of 9	NP_000162.2
	GLRA1	NM_001146040.2		c.921delT	p.Tyr307fs	frameshift	Exon 8 of 9	NP_001139512.1
	GLRA1	NM_001292000.2		c.672delT	p.Tyr224fs	frameshift	Exon 7 of 8	NP_001278929.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.921delT	p.Tyr307fs	frameshift	Exon 8 of 9	ENSP00000274576.5
	GLRA1	ENST00000455880.2	TSL:1	c.921delT	p.Tyr307fs	frameshift	Exon 8 of 9	ENSP00000411593.2
	GLRA1	ENST00000462581.6	TSL:1	n.*679delT		non_coding_transcript_exon	Exon 7 of 8	ENSP00000430595.1

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

Oct 04, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Hereditary hyperekplexia Pathogenic:1

Jul 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281864921; hg19: chr5-151208619;