Submissions for variant NM_000719.7(CACNA1C):c.3577G>A (p.Ala1193Thr)

dbSNP: rs1251955384

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001658952	SCV001874203	uncertain significance	not provided	2021-06-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
New York Genome Center	RCV003227983	SCV003925286	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2022-09-09	criteria provided, single submitter	clinical testing	The c.3577G>A variant has not previously been reported in the literature in individuals affected with CACNA1C related disorders. It is present as one heterozygous allele (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. This variant has been deposited in ClinVar as Variant of Uncertain Significance [ClinVar ID: 1254770]. The c.3577G>A variant islocated in exon 28 of this 47-exon gene and is predicted to replace an evolutionarily conserved alanine amino acid with threonine at position 1193 of the encoded protein. In silico predictions are in favor of damaging effect for p.(Ala1193Thr) variant [(CADD v1.6 = 29.1, REVEL = 0.876)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.3577G>A p.(Ala1193Thr) variant identified in CACNA1C is classified as a Variant of Uncertain Significance.