Submissions for variant NM_001167623.2(CACNA1C):c.1216G>A (p.Gly406Arg)

dbSNP: rs786205745

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170769	SCV000223324	pathogenic	not provided	2014-01-28	criteria provided, single submitter	clinical testing	p.Gly406Arg (GGA>AGA): c.1216 G>A in exon 8 of the CACNA1C gene (NM_001167625.1). The G406R mutation in the CACNA1C gene has been reported previously in association with Timothy syndrome (Splawski I et al., 2004; Yarotskyy V et al., 2009). Splawski et al. reported G406R as a de novo mutation in 11 unrelated individuals with Timothy syndrome and additionally in two siblings that inherited G406R as a result of germline mosaicism (Splawski I et al., 2004). In this same study, G406R was absent in 360 control alleles and expression of the CACNA1C gene was found in multiple tissue types that correlate to the organ systems affected in Timothy syndrome. Moreover, G406R was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Gly406 residue is highly conserved across species and functional studies identified that G406R has a significant effect on calcium ion channel currents leading to action potential prolongation (Splawski I et al., 2004). G406R is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. In summary, G406R in the CACNA1C gene is interpreted as a disease-causing mutation. The variant is found in ARRHYTHMIA panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385670	SCV001585613	pathogenic	Long QT syndrome	2020-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 406 of the CACNA1C protein (p.Gly406Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. The c.1216G>A variant occurs in alternate transcript NM_001129840.1, which corresponds to position c.1114-304G>A in NM_000719.6, the primary transcript listed in the Methods. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with atypical Timothy syndrome (TS2) including affected individuals where the variant was observed de novo (PMID: 28371864, 15863612, 26227324, 26301350). This variant is also known as G406R in exon 9 in the literature. ClinVar contains an entry for this variant (Variation ID: 190633). Experimental studies have shown that this missense change results in reduced CaV1.2 channel inactivation (PMID: 19074970, 15863612, 26822303, 18250309, 22990809). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498853	SCV002805930	likely pathogenic	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-10-04	criteria provided, single submitter	clinical testing
GeneReviews	RCV000192272	SCV000240237	not provided	Timothy syndrome		no assertion provided	literature only	Timothy syndrome phenotype with or without syndactyly