ClinVar Miner

Submissions for variant NM_021098.3(CACNA1H):c.4736G>A (p.Arg1579Gln)

gnomAD frequency: 0.00004  dbSNP: rs367947771
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001057729 SCV001222237 uncertain significance Idiopathic generalized epilepsy; Hyperaldosteronism, familial, type IV 2022-09-20 criteria provided, single submitter clinical testing 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1H protein function. ClinVar contains an entry for this variant (Variation ID: 853002). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is present in population databases (rs367947771, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1579 of the CACNA1H protein (p.Arg1579Gln).
Athena Diagnostics RCV001288107 SCV001474971 uncertain significance not provided 2020-04-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509602 SCV002819904 uncertain significance not specified 2024-04-25 criteria provided, single submitter clinical testing Variant summary: CACNA1H c.4736G>A (p.Arg1579Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 244164 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1H causing Idiopathic Generalized Epilepsy (4.5e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4736G>A in individuals affected with Idiopathic Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 853002). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV004601346 SCV005099706 uncertain significance Inborn genetic diseases 2024-05-13 criteria provided, single submitter clinical testing The c.4736G>A (p.R1579Q) alteration is located in exon 25 (coding exon 24) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 4736, causing the arginine (R) at amino acid position 1579 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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