The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!


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
More

Pathogenic

Met criteria codes 5
PS2_Moderate PM1_Strong PM2_Supporting PS4 PS3
Not Met criteria codes 14
BA1 BP5 BP4 BP1 BP2 BS4 BS3 BS1 PP3 PP2 PP4 PP1 PS1 PM5

Evidence Links 1

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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.
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)
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
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)

Not Met criteria codes
BA1
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
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
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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)
PP2
Not applicable as more robust contraint measures are used.
PP4
Accounted for under PS2/PM6/PS4
PP1
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
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)
Curation History
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