rs121908212
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001127222.2(CACNA1A):c.1994C>T(p.Thr665Met) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T665T) has been classified as Likely benign.
Frequency
Consequence
NM_001127222.2 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 | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.1994C>T | p.Thr665Met | missense_variant | 16/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.1994C>T | p.Thr665Met | missense_variant | 16/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2021 | Published functional studies demonstrate that the variant leads to loss-of-function for the P/Q-type channel activity, which significantly alters channel inactivation kinetics resulting in defective voltage-dependent gating to support calcium influx (Kraus et al., 1998; Barrett et al., 2005; Tao et al., 2012); Not observed 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: 30180405, 28717674, 10024348, 22136990, 24270521, 25274239, 22190617, 9488686, 22969264, 22000314, 25266619, 24498617, 27290639, 11971066, 11814735, 28169007, 18279427, 15795222, 12056940, 10987655, 8898206, 9915947, 12756131, 28856914, 29915382, 29486580, 31824404, 31692161, 14718690, 11439943, 31935766, 30063100, 31115040, 30027842) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 14, 2019 | PS3, PS4_Moderate, PM2, PP1, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 21, 2023 | This variant has been identified in individuals with familial hemiplegic migraine (FHM) and/or cerebellar ataxia, and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:10024348, 22190617, 9488686) - |
Migraine, familial hemiplegic, 1 Pathogenic:4Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 24, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | May 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Aug 30, 2016 | - - |
Episodic ataxia type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 08, 2015 | - - |
Pathogenic, criteria provided, single submitter | research | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Developmental and epileptic encephalopathy, 42 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11814735). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10024348, 22190617, 9488686). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96>=0.6). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2023 | Variant summary: CACNA1A c.1997C>T (p.Thr666Met) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247906 control chromosomes. c.1997C>T has been reported in the literature in multiple individuals affected with Familial Hemiplegic Migraine (example, Ducros_2001, Garcia-Baro-Huarte_2014). These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function (example, Hans_1999). The most pronounced variant effect results in decreased density of functional channels and their unitary conductance consistent with a loss of function mechanism od disease. The following representative publications have been ascertained in the context of this evaluation (PMID: 11439943, 25266619, 10024348). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 666 of the CACNA1A protein (p.Thr666Met). This variant is present in population databases (rs121908212, gnomAD 0.008%). This missense change has been observed in individuals with hemiplegic migraine (PMID: 8898206, 11814735, 11971066, 24270521, 25274239, 28169007). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8488). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 9488686, 10024348). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2023 | The c.1997C>T (p.T666M) alteration is located in exon 16 (coding exon 16) of the CACNA1A gene. This alteration results from a C to T substitution at nucleotide position 1997, causing the threonine (T) at amino acid position 666 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been described in many individuals with a wide clinical spectrum of symptoms including: migraines, hemiplegia, comas, progressive cognitive dysfunction, and progressive cerebellar ataxia, in both the individual and familial forms (Ophoff, 1996; Wada, 2002; Kirchmann, 2006; Choi, 2012; García-Baró-Huarte, 2014; Kierdaszuk, 2017; Indelicato, 2019; Li, 2019; Sun, 2019; Ngo, 2020). In addition, this alteration has been referred to as the most common mutation found in CACNA1A, accounting for 40% of unrelated cases of CACNA1A-related familial hemiplegic migraine (Choi, 2012). This amino acid position is highly 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). In vitro studies showed defective voltage-dependent gating associated with the p.T666M pathogenic mutation (Barrett, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Migraine, sporadic hemiplegic, with progressive cerebellar ataxia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 24, 2005 | - - |
Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Pathogenic and reported on 08-01-2018 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Familial hemiplegic migraine Other:1
not provided, no classification provided | literature only | GeneReviews | - | Most common pathogenic variant with no evidence for founder effect - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at