Submissions for variant NM_001127222.2(CACNA1A):c.4175T>C (p.Val1392Ala)

dbSNP: rs2144767386

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002034426	SCV002310889	likely pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2021-02-28	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val1393 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28007337, 30283815, 31468518). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. This variant has not been reported in the literature in individuals with CACNA1A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 1393 of the CACNA1A protein (p.Val1393Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	RCV002466277	SCV002761262	likely pathogenic	Developmental and epileptic encephalopathy, 42	2022-02-03	criteria provided, single submitter	clinical testing