rs1057517711
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_ModeratePM1PM2PM5PP2PP5_Very_Strong
The NM_000719.7(CACNA1C):c.1553G>A(p.Arg518His) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,595,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | ENST00000399655.6 | NP_000710.5 | |
CACNA1C | NM_001167623.2 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 5 | NM_001167623.2 | ENSP00000382512.1 | ||
CACNA1C | ENST00000399655.6 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | NM_000719.7 | ENSP00000382563.1 | ||
CACNA1C | ENST00000682544.1 | c.1643G>A | p.Arg548His | missense_variant | 12/50 | ENSP00000507184.1 | ||||
CACNA1C | ENST00000406454.8 | c.1553G>A | p.Arg518His | missense_variant | 12/48 | 5 | ENSP00000385896.3 | |||
CACNA1C | ENST00000399634.6 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 5 | ENSP00000382542.2 | |||
CACNA1C | ENST00000683824.1 | c.1718G>A | p.Arg573His | missense_variant | 13/48 | ENSP00000507867.1 | ||||
CACNA1C | ENST00000347598.9 | c.1553G>A | p.Arg518His | missense_variant | 12/49 | 1 | ENSP00000266376.6 | |||
CACNA1C | ENST00000344100.7 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000341092.3 | |||
CACNA1C | ENST00000327702.12 | c.1553G>A | p.Arg518His | missense_variant | 12/48 | 1 | ENSP00000329877.7 | |||
CACNA1C | ENST00000399617.6 | c.1553G>A | p.Arg518His | missense_variant | 12/48 | 5 | ENSP00000382526.1 | |||
CACNA1C | ENST00000682462.1 | c.1643G>A | p.Arg548His | missense_variant | 12/47 | ENSP00000507105.1 | ||||
CACNA1C | ENST00000683781.1 | c.1643G>A | p.Arg548His | missense_variant | 12/47 | ENSP00000507434.1 | ||||
CACNA1C | ENST00000683840.1 | c.1643G>A | p.Arg548His | missense_variant | 12/47 | ENSP00000507612.1 | ||||
CACNA1C | ENST00000683956.1 | c.1643G>A | p.Arg548His | missense_variant | 12/47 | ENSP00000506882.1 | ||||
CACNA1C | ENST00000399638.5 | c.1553G>A | p.Arg518His | missense_variant | 12/48 | 1 | ENSP00000382547.1 | |||
CACNA1C | ENST00000335762.10 | c.1628G>A | p.Arg543His | missense_variant | 13/48 | 5 | ENSP00000336982.5 | |||
CACNA1C | ENST00000399606.5 | c.1553G>A | p.Arg518His | missense_variant | 12/48 | 1 | ENSP00000382515.1 | |||
CACNA1C | ENST00000399621.5 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000382530.1 | |||
CACNA1C | ENST00000399637.5 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000382546.1 | |||
CACNA1C | ENST00000402845.7 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000385724.3 | |||
CACNA1C | ENST00000399629.5 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000382537.1 | |||
CACNA1C | ENST00000682336.1 | c.1628G>A | p.Arg543His | missense_variant | 13/47 | ENSP00000507898.1 | ||||
CACNA1C | ENST00000399591.5 | c.1553G>A | p.Arg518His | missense_variant | 12/46 | 1 | ENSP00000382500.1 | |||
CACNA1C | ENST00000399595.5 | c.1553G>A | p.Arg518His | missense_variant | 12/46 | 1 | ENSP00000382504.1 | |||
CACNA1C | ENST00000399649.5 | c.1553G>A | p.Arg518His | missense_variant | 12/46 | 1 | ENSP00000382557.1 | |||
CACNA1C | ENST00000399597.5 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000382506.1 | |||
CACNA1C | ENST00000399601.5 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000382510.1 | |||
CACNA1C | ENST00000399641.6 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000382549.1 | |||
CACNA1C | ENST00000399644.5 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | 1 | ENSP00000382552.1 | |||
CACNA1C | ENST00000682835.1 | c.1553G>A | p.Arg518His | missense_variant | 12/47 | ENSP00000507282.1 | ||||
CACNA1C | ENST00000683482.1 | c.1544G>A | p.Arg515His | missense_variant | 12/47 | ENSP00000507169.1 | ||||
CACNA1C | ENST00000682686.1 | c.1553G>A | p.Arg518His | missense_variant | 12/46 | ENSP00000507309.1 | ||||
CACNA1C | ENST00000480911.6 | n.*160G>A | non_coding_transcript_exon_variant | 10/27 | 5 | ENSP00000437936.2 | ||||
CACNA1C | ENST00000480911.6 | n.*160G>A | 3_prime_UTR_variant | 10/27 | 5 | ENSP00000437936.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1443646Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1AN XY: 716136
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 29, 2024 | Published functional studies demonstrate reduction in current density combined with increased window current and loss of inactivation (PMID: 26253506); 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; This variant is associated with the following publications: (PMID: 27390944, 30984024, 30025578, 30027834, 35862440, 32161207, 30681346, 34079780, 35352813, 31110529, 31408100, 36252119, 34999275, 36578016, 37614386, 26253506, 31430211) - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 26, 2023 | - - |
Long qt syndrome 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Region Ostergotland | Jan 11, 2024 | PS3, PM5, PM2, PP3 - |
Timothy syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 29, 2022 | - - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 518 of the CACNA1C protein (p.Arg518His). This variant is present in population databases (no rsID available, gnomAD 0.3%). This missense change has been observed in individuals with long QT syndrome or a complex phenotype of long QT syndrome and hypertrophic cardiomyopathy (PMID: 26253506, 30025578, 31408100, 32161207). ClinVar contains an entry for this variant (Variation ID: 372313). 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 CACNA1C protein function. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 26253506). This variant disrupts the p.Arg518 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26253506; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 28, 2024 | The c.1553G>A (p.R518H) alteration is located in exon 12 (coding exon 12) of the CACNA1C gene. This alteration results from a G to A substitution at nucleotide position 1553, causing the arginine (R) at amino acid position 518 to be replaced by a histidine (H). for CACNA1C-related long QT syndrome/Timothy syndrome; however, its clinical significance for CACNA1C-related neurodevelopmental disorder is uncertain. Based on data from gnomAD, the A allele has an overall frequency of 0.003% (1/31394) total alleles studied. The highest observed frequency was <0.001% of alleles. This variant was reported in multiple individuals with features consistent with CACNA1C-related long QT syndrome/Timothy syndrome (Fukuyama, 2020, Bagnall, 2018, external communication). This amino acid position is well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Wu, 2016, Mellor, 2019, Boczek, 2015, Korkosh, 2019). In an assay testing CACNA1C function, this variant showed a functionally abnormal result (Boczek, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2022 | Variant summary: CACNA1C c.1553G>A (p.Arg518His) results in a non-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 was absent in 219196 control chromosomes. c.1553G>A has been reported in the literature in individuals affected with Arrhythmia. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant disrupts the normal function. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hypertrophic cardiomyopathy 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Apr 19, 2017 | The CACNA1C Arg518His variant had been identified in a few probands with mixed phenotypes of Long QT, congenital heart defects and HCM (Boczek NJ, et al., 2015; Genedx, personal communication) and has been found to segregate in 2 families with varying phenotypes (Boczek NJ, et al., 2015). In vitro functional analysis using whole cell patch clamping confirmed the loss of current density and inactivation in combination with increased window and later voltage gated calcium channel current (Boczek NJ, et al., 2015), however this study may not necessarily reflect biological function and future studies will be useful to validate these findings. The variant is present a singleton event in the Exome Aggregation Consortium dataset (MAF= 0.00003230, http://exac.broadinstitute.org/). We identified this variant in a patient diagnosed with HCM in their adoloscence, the patient had a known family history of disease and a prolonged QT was noted when the patient was in his 40s. The probands affected son also harbours this variant. He was diagnosed with HCM at 2 months. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to have deleterious effect. In summary, based on a few proband's reported with similar phenotypes, strong segregation data, rarity in general population databases, as well supportive in silico tools in combination with a functional study suggestive of an affect on protein function, we classify the CACNA1C Arg518His as "likely pathogenic". - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at