Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1PM1PM2PM5PP2PP3PP5
The NM_000719.7(CACNA1C):c.4087G>T(p.Val1363Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1363M) has been classified as Likely pathogenic.
CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]
Verdict is Pathogenic. Variant got 13 ACMG points.
PS1
Transcript NM_000719.7 (CACNA1C) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 522828
PM1
In a topological_domain Extracellular (size 50) in uniprot entity CAC1C_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000719.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-2653847-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 450063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, CACNA1C
PP3
MetaRNN computational evidence supports a deleterious effect, 0.812
PP5
Variant 12-2653847-G-T is Pathogenic according to our data. Variant chr12-2653847-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1164022.Status of the report is no_assertion_criteria_provided, 0 stars.