ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.3803C>T (p.Pro1268Leu)

gnomAD frequency: 0.00001  dbSNP: rs1057522815
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441511 SCV000529604 uncertain significance not provided 2022-12-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV003766337 SCV004605984 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2023-01-18 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1269 of the CACNA1A protein (p.Pro1269Leu). ClinVar contains an entry for this variant (Variation ID: 387528). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV004783782 SCV005397817 uncertain significance Spinocerebellar ataxia type 6 2024-04-26 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (C>T) at position 3803 of the coding sequence of the CACNA1A gene that results in a proline to leucine amino acid change at residue 1268 of the calcium voltage-gated channel subunit alpha1 A protein. This residue falls in the extracellular portion of domain III (UniProt). This is a previously reported variant (ClinVar 387528) that has not been observed in individuals affected by a CACNA1A-related disorder in the published literature, to our knowledge. This variant is present in 4 of 1613850 alleles (0.0002%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Pro1268 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3

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