Variant: NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr)

CA318033

207024 (ClinVar)

Gene: SCN2A

Condition: complex neurodevelopmental disorder

Inheritance Mode: Autosomal dominant inheritance

UUID: 6069a6a1-2957-454e-9774-80e2a3fba60c

Approved on: 2024-05-07

Published on: 2024-05-07

HGVS expressions

NM_001040142.2:c.5317G>A
NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr)
NC_000002.12:g.165389123G>A
CM000664.2:g.165389123G>A
NC_000002.11:g.166245633G>A
CM000664.1:g.166245633G>A
NC_000002.10:g.165953879G>A
NG_008143.1:g.154722G>A
ENST00000631182.3:c.5317G>A
ENST00000375437.7:c.5317G>A
ENST00000636071.2:c.5317G>A
ENST00000636135.1:c.*3636G>A
ENST00000636384.2:c.*3304G>A
ENST00000636662.2:c.*5840G>A
ENST00000636769.1:c.*3259G>A
ENST00000636985.2:c.4921G>A
ENST00000637266.2:c.5317G>A
ENST00000283256.10:c.5317G>A
ENST00000375427.4:c.5317G>A
ENST00000375437.6:c.5317G>A
ENST00000480032.4:n.8748G>A
ENST00000631182.2:c.5317G>A
NM_001040142.1:c.5317G>A
NM_001040143.1:c.5317G>A
NM_021007.2:c.5317G>A
NM_001040143.2:c.5317G>A
NM_001371246.1:c.5317G>A
NM_001371247.1:c.5317G>A
NM_021007.3:c.5317G>A

Pathogenic

• Met criteria codes: PS3 PS4 PM1_Strong PM2_Supporting PS2_Moderate

• Not Met criteria codes: BP4 BP1 BP2 BP5 PS1 BA1 PP1 PP2 PP3 PP4 PM5 BS1 BS4 BS3

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 SCN2A Version 1.0.0

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.5317G>A (NM_001040142.2) variant in SCN2A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1773 (p.Ala1773Thr). This variant has been reported in 9 probands with complex neurodevelopmental disorder (PMIDs: 34758253, 33000761, 28947817, 29655203, 31440721, 31785789, 34469436, 32400968, 35431799), including as a de novo occurrence with confirmed parental relationships in 2 individual(s) (PMIDs: 31785789, 32400968) and as a de novo occurrence with assumed parental relationships in 2 individuals PMID: 33000761, 35431799). This variant is absent from gnomAD v2.1.1. Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968). This variant resides within a region of SCN2A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as pathogenic for complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS3, PS4, PS2, PM1, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications v1.0; approved 5/9/23).

Met criteria codes

• PS3: Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968)(PS3_Strong)
• PS4: This variant has been reported in 9 probands meeting complex neurodevelopmental disorder. Four of these probands are de novo and counted for the PS2 criteria, leaving five probands (PS4_Strong); PMIDs: 34758253, 33000761, 28947817, 29655203, 31440721, 31785789, 34469436, 32400968, 35431799
• PM1_Strong: This variant resides within a region of SCN2A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1_Strong)
• PM2_Supporting: This variant is absent from gnomAD v[20210610] (PM2_Supporting)
• PS2_Moderate: This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individual(s) and with assumed de novo variants with neurodevelopmental phenotype in 2 individuals (PS2_Moderate) PMID: 31785789, 32400968, 33000761, and 35431799.

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: 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
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: Not applicable as more robust contraint measures are used.
• PP3: Not applying PP3 since this variant meets PM1_strong per VCEP specifications, but computational predictor REVEL gives a score of 0.94, which is above the threshold that correlates with impact to moderate function per the specifications (PP3_Moderate)
• PP4: Accounted for under PS2/PM6/PS4
• PM5: Another missense variant [c.5318 C>T, p.Ala1773Val] in the same codon has been reported in patients with complex neurodevelopmental disorder (PMIDs: 34992632, 28379373, 27824329, ClinVar Variation ID: 520893]. However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Epilepsy Sodium Channel VCEP (PM5 not met)
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline