Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_006922.4(SCN3A):c.2624T>C (p.Ile875Thr)

CA16043377

373960 (ClinVar)

Gene: SCN3A

Condition: developmental and epileptic encephalopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2ec0b468-966c-4f4a-8b2b-75d4a680b3f1

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_006922.4:c.2624T>C

NM_006922.4(SCN3A):c.2624T>C (p.Ile875Thr)

NC_000002.12:g.165130238A>G

CM000664.2:g.165130238A>G

NC_000002.11:g.165986748A>G

CM000664.1:g.165986748A>G

NC_000002.10:g.165694994A>G

NG_042289.1:g.78851T>C

ENST00000706067.1:c.2573T>C

ENST00000283254.12:c.2624T>C

ENST00000638473.1:c.*465T>C

ENST00000639244.1:c.2573T>C

ENST00000640652.1:c.2573T>C

ENST00000658209.1:c.722T>C

ENST00000668657.1:c.2486T>C

ENST00000283254.11:c.2624T>C

ENST00000360093.7:c.2624T>C

ENST00000409101.7:c.2477T>C

ENST00000440431.6:c.2477T>C

NM_001081676.1:c.2477T>C

NM_001081677.1:c.2477T>C

NM_006922.3:c.2624T>C

NM_001081676.2:c.2477T>C

NM_001081677.2:c.2477T>C

Pathogenic

PS2_Very Strong PS3 PM1 PM2_Supporting PM6

BS1 BP4 BA1 PP3

Evidence Links 1

Expert Panel

Epilepsy Sodium Channel VCEP

Criteria Specification Information

Criteria Specification: ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.2624T>C variant in SCN3A is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 875 (p.Ile875Thr). The variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) with DEE (PMIDs: 29740860, 29466837) (PS2_Very Strong) and as a de novo occurrance with unconfirmed parental relationship in a least 2 individuals with DEE (PMIDs: 29286531, 28191890) (PM6_Moderate), with additional case evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Studies have observed that when expressed in mammalian cells in culture, this variant causes a gain-of-function effect on the mutant channels as evidenced by a significant leftward/hyperpolarized shift in the voltage dependence of activation, an increase in the persistent/inactivating current, and a rightward/depolarizing shift in the voltage of inactivation (PS3; PMID: 29466837). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant developmental and epilepstic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_VS, PM6_Moderate, PM2_Supporting, PS3. (Version 1; July 7, 2023).

PS2_Very Strong

This variant has been identified as de novo via trio exome sequencing in at least 4 patients with consistent phenotypes.

PS3

Heterologous expression with voltage clamping showed a difference that exceeded the threshold for Strong in multiple biophysical parameters: Voltage dependence of activation shifted 10.9mV (WT -26.2; mutant -37.1), threshold 2.2mV. Voltage dependence of inactivation shifted 9.7mV (WT 10.2, mutant 19.9), threshold 4.1mV. Persistant current (WT 2.6, mutant 18.0) >135% of WT.

Voltage dependence of activation shifted 10.9mV (WT -26.2; mutant -37.1), threshold 2.2mV. Voltage dependence of inactivation shifted 9.7mV (WT 10.2, mutant 19.9), threshold 4.1mV. Persistant current (WT 2.6, mutant 18.0) >135% of WT. PubMed:29466837

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2_Supporting

This variant is absent from gnomAD v2.1.1.

PM6

This variant has been identified as de novo with confirmed parental relationships in at least 2 patients with consistent phenotypes.

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

The in-silico REVEL score for this variant is 0.976 which meets the criteria for PP3_Moderate but was not applied as PM1_Strong was already reached.

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