Submissions for variant NM_001127222.2(CACNA1A):c.1994C>T (p.Thr665Met)

dbSNP: rs121908212

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000504541	SCV000593815	pathogenic	Episodic ataxia type 2	2015-10-08	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000009009	SCV000598107	pathogenic	Migraine, familial hemiplegic, 1	2016-08-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000516650	SCV000612511	pathogenic	not provided	2023-04-21	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802118	SCV000941934	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-10-30	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000009009	SCV001150034	pathogenic	Migraine, familial hemiplegic, 1	2021-05-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000516650	SCV001248629	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000516650	SCV001446542	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000516650	SCV001713791	pathogenic	not provided	2019-07-14	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM2, PP1, PP3
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000009009	SCV001994820	pathogenic	Migraine, familial hemiplegic, 1	2021-10-28	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000504541	SCV002053927	pathogenic	Episodic ataxia type 2		criteria provided, single submitter	research
3billion	RCV002051776	SCV002318456	pathogenic	Developmental and epileptic encephalopathy, 42	2022-03-22	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000516650	SCV002512902	pathogenic	not provided	2021-04-02	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV002415406	SCV002717687	pathogenic	Inborn genetic diseases	2023-03-20	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002051776	SCV004020795	pathogenic	Developmental and epileptic encephalopathy, 42	2023-06-17	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000009009	SCV000029223	pathogenic	Migraine, familial hemiplegic, 1	2005-06-24	no assertion criteria provided	literature only
OMIM	RCV000009010	SCV000029225	pathogenic	Migraine, sporadic hemiplegic, with progressive cerebellar ataxia	2005-06-24	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000009009	SCV000090843	not provided	Migraine, familial hemiplegic, 1		no assertion provided	not provided
GeneReviews	RCV001533159	SCV001748978	not provided	Familial hemiplegic migraine		no assertion provided	literature only	Most common pathogenic variant with no evidence for founder effect
GenomeConnect - Brain Gene Registry	RCV003233067	SCV003931189	not provided	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1		no assertion provided	phenotyping only	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/.