VP-R-2026-003

GLRA1 c.1214G>A

Hereditary hyperekplexia

Needs reviewMedium

Classification change

Then2022

Uncertain significance

As reported

Science changed

Now2026

Benign

Multiple submitters, no conflicts

Regional conflict

Variant

Gene: GLRA1
HGVS (coding): c.1214G>A
Protein: p.Arg405Gln
ClinVar: VCV000352307
dbSNP: rs199561280
Panel: Paediatric neurology panel
Molecular consequence: missense variant

Patient impact

Records carrying this variant.

VP-109140-4 · Paediatric Neurology14 Nov 2022Dr. S. Aziz

How the interpretation changed

GLRA1 c.1214G>A — the DNA is unchanged. The evidence around it is not.

2022Genetic test performedFirst record on file carrying GLRA1 c.1214G>A.
2022Reported as uncertain significanceReported in a neonatal hyperekplexia work-up. Classified as uncertain pending segregation data.
2026Submissions accumulated4 independent submissions now contribute to the classification.
2026Classification now benignLast evaluated 3 Feb 2026 · Multiple submitters, no conflicts.
TodayVariantPulse identified the affected recordsOne historical record carries this variant and was flagged for clinical review.

Evidence summary

Decision support

Global and regional evidence disagree on GLRA1 c.1214G>A. The global consensus is benign, drawn from 4 submissions. The regional index asserts likely pathogenic on 9 observations across a cohort of 4,120. One source places this variant in the clinically actionable band and the other does not, which is the form of disagreement most likely to change a care decision. One record on file carries this variant and has not yet been reassessed.

Composed from the structured fields of the records cited on this page. Requires clinical verification before it informs any decision.

Evidence by source

Each source is shown as it reports itself. VariantPulse does not merge them into a single verdict.

Source	Classification	Review level	Last updated	Strength
ClinVar4 submissions on record.	Benign	Multiple submitters, no conflicts	3 Feb 2026	Moderate2 of 4 review criteria met	VCV000352307
Population frequencyHighest reported allele frequency carried on the source record.	0.00031	Trans-Omics for Precision Medicine (TOPMed)	3 Feb 2026	Reference observation
LiteraturePublications linked to this variant record.	5 indexed publications	PubMed index	Latest 2017	Supporting context
Regional Evidence IndexModelled regional aggregation maintained inside this workspace	Likely pathogenic	9 regional observations	22 Jan 2026	Cohort 4,120
This institutionThe interpretation issued to the patient at the time of testing.	Uncertain significance	Internal report	14 Nov 2022	On record

Cited publications

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. — Genet Med 2017 · PMID 28492532
Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. — BMC Med Genomics 2016 · PMID 27435318
Whole exome sequencing diagnosis of inborn errors of metabolism and other disorders in United Arab Emirates. — Orphanet J Rare Dis 2016 · PMID 27391121
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. — Genet Med 2015 · PMID 25741868
Hereditary Hyperekplexia Overview. — University of Washington, Seattle 1993 · PMID 20301437

Global and regional evidence

Regional conflict

Global

Benign

Submissions: 4
Review status: Multiple submitters, no conflicts
Last evaluated: 3 Feb 2026
Reference frequency: 3.10e-4

Read from ClinVar, which aggregates submissions dominated by European-ancestry cohorts.

Regional

Likely pathogenic

Observations: 9
Cohort size: 4,120
Last updated: 22 Jan 2026
Regional frequency: 1.10e-3

Modelled regional aggregation maintained inside this workspace.

VariantPulse analysis

One source places this variant in the clinically actionable band and the other does not. Observed in nine regional probands with a consistent neonatal hyperekplexia phenotype, several from consanguineous families where the change segregated with disease. Published work reports that GLRA1 genotype in hyperekplexia tracks with ethnicity, which is the mechanism by which a globally benign reading and a regional pathogenic reading can both be internally consistent.

VariantPulse recommends manual review due to conflicting interpretation across evidence sources. It does not rank one source above the other.

Ethnicity can predict GLRA1 genotypes in hyperekplexia. — J Neurol Neurosurg Psychiatry 2015 · PMID 24970905
Hereditary Hyperekplexia in Saudi Arabia. — Pediatr Neurol 2022 · PMID 35841715
Hyperekplexia in Kurdish families: a possible GLRA1 founder mutation. — Neurology 2006 · PMID 16832093

How VariantPulse reached this resultEight steps, each one inspectable

1Historical record retrievedGLRA1 c.1214G>A reported as Uncertain significance on 2022-11-14.
2Variant normalisedResolved to ClinVar VCV000352307 (rs199561280) and keyed as GLRA1:c.1214G>A.
3Current evidence retrievedRead live from ClinVar: Benign/Likely benign, 4 submissions, criteria provided, multiple submitters, no conflicts.
4Classification difference detectedRecorded interpretation normalised to Uncertain significance. Current interpretation normalised to Benign. Evidence moved toward a benign interpretation.
5Regional sources comparedRegional index asserts Likely pathogenic across 9 observations. One source places this variant in the clinically actionable band and the other does not.
6Impacted records identified12,482 findings checked; 1 carries this variant.
7Evidence brief generatedComposed from the structured fields of the cited records above.
8Human review requestedVariantPulse does not change any record. A clinician decides what happens next.

Review priority

A triage signal for the queue. Not a clinical risk score, and not a statement about any individual.

+30Regional evidence conflictsRegional and global sources reach different conclusions.
+51 record on fileHistorical results carrying this variant that a reviewer would reassess.

Ordering score35

Case notes

No notes on this case yet.

Recommendation

Manual review recommended: global and regional sources disagree, and VariantPulse does not rank one above the other. A clinician should weigh both against the patient context.

Approving records a review decision inside VariantPulse. It does not write to any patient record and does not issue a diagnosis.

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Case detail

Case: VP-R-2026-003
Raised: just now
Assigned: Unassigned
Evidence source: ClinVar (live)
Records impacted: 1

Decision support only. Final interpretation remains with the qualified clinical team.

Affected records in full

Record	Age band	Test date	As reported	Current	Department	Clinical owner	Last contact	Review state
VP-10914	0-4	14 Nov 2022	VUS	Benign	Paediatric Neurology	Dr. S. Aziz	3y ago	Not reviewed

Source

Classification

Review level

Last updated

Strength

ClinVar4 submissions on record.

Benign

Multiple submitters, no conflicts

3 Feb 2026

Moderate

VCV000352307

Population frequencyHighest reported allele frequency carried on the source record.

0.00031

Trans-Omics for Precision Medicine (TOPMed)

3 Feb 2026

Reference observation

LiteraturePublications linked to this variant record.

5 indexed publications

PubMed index

Latest 2017

Supporting context

Regional Evidence IndexModelled regional aggregation maintained inside this workspace

Likely pathogenic

9 regional observations

22 Jan 2026

Cohort 4,120

This institutionThe interpretation issued to the patient at the time of testing.

Uncertain significance

Internal report

14 Nov 2022

On record

Record

Age band

Test date

As reported

Current

Department

Clinical owner

Last contact

Review state

VP-10914

0-4

14 Nov 2022

VUS

Benign

Paediatric Neurology

Dr. S. Aziz

3y ago

Not reviewed