rs1553998291

Variant names:

• chr4-157143853-CGG-GATGATGGGGGT
• rs1553998291
• NM_000824.5:c.798_800delCGGinsGATGATGGGGGT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_000824.5(GLRB):​c.798_800delCGGinsGATGATGGGGGT​(p.Gly267delinsMetMetGlyVal) variant causes a missense, disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRB NM_000824.5 missense, disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93

Genes affected

GLRB (HGNC:4329): (glycine receptor beta) This gene encodes the beta subunit of the glycine receptor, which is a pentamer composed of alpha and beta subunits. The receptor functions as a neurotransmitter-gated ion channel, which produces hyperpolarization via increased chloride conductance due to the binding of glycine to the receptor. Mutations in this gene cause startle disease, also known as hereditary hyperekplexia or congenital stiff-person syndrome, a disease characterized by muscular rigidity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000824.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRB	NM_000824.5	c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense_variant, disruptive_inframe_insertion		ENST00000264428.9	NP_000815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRB	ENST00000264428.9	c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense_variant, disruptive_inframe_insertion		1	NM_000824.5	ENSP00000264428.4
GLRB	ENST00000509282.1	c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense_variant, disruptive_inframe_insertion		1		ENSP00000427186.1
GLRB	ENST00000541722.5	c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense_variant, disruptive_inframe_insertion		5		ENSP00000441873.1
GLRB	ENST00000512619.5	c.123-26579_123-26577delCGGinsGATGATGGGGGT		intron_variant	Intron 2 of 2	3		ENSP00000425433.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 2 Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.798_800delinsGATGATGGGGGT, is a complex sequence change that results in the deletion of 1 amino acid and insertion of 4 amino acid(s) in the GLRB protein (p.Gly267delinsMetMetGlyVal). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hyperekplexia (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553998291; hg19: chr4-158065005;