Submissions for variant NM_001128840.3(CACNA1D):c.5813C>T (p.Pro1938Leu)

gnomAD frequency: 0.00001  dbSNP: rs770886605

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000611554	SCV000712226	likely benign	not specified	2016-06-20	criteria provided, single submitter	clinical testing	p.Pro1958Leu in exon 47 of CACNA1D: This variant is not expected to have clinica l significance due to a lack of conservation across species, including mammals. Of note, 8 mammals have a leucine (Leu) at this position despite high nearby ami no acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has been identified in 1/8586 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs770886605).
Genetic Services Laboratory, University of Chicago	RCV000611554	SCV002070767	uncertain significance	not specified	2020-08-07	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CACNA1D gene demonstrated a sequence change, c.5873C>T, in exon 47 that results in an amino acid change, p.Pro1958Leu. This sequence change does not appear to have been previously described in patients with CACNA1D-related disorders and has has been described in the gnomAD database with a low population frequency of 0.0044% (dbSNP rs770886605). The p.Pro1958Leu change affects a moderately conserved amino acid residue located in a domain of the CACNA1D protein that is not known to be functional. The p.Pro1958Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
GeneDx	RCV002289894	SCV002578489	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002289894	SCV003508573	uncertain significance	not provided	2024-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1958 of the CACNA1D protein (p.Pro1958Leu). This variant is present in population databases (rs770886605, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 505106). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV002289894	SCV003830338	uncertain significance	not provided	2020-05-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002289894	SCV004226123	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	BP4, PP2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000611554	SCV005395644	uncertain significance	not specified	2024-09-05	criteria provided, single submitter	clinical testing	Variant summary: CACNA1D c.5873C>T (p.Pro1958Leu) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain (IPR031688) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 247672 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1D causing Sinoatrial Node Dysfunction And Deafness, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5873C>T in individuals affected with Sinoatrial Node Dysfunction And Deafness and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 505106). Based on the evidence outlined above, the variant was classified as uncertain significance.