19-46608584-A-C

Position:

• chr19-46608584-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_005184.4(CALM3):​c.281A>C​(p.Asp94Ala) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM3 NM_005184.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.21

Genes affected

CALM3 (HGNC:1449): (calmodulin 3) This gene encodes a member of a family of proteins that binds calcium and functions as a enzymatic co-factor. Activity of this protein is important in the regulation of the cell cycle and cytokinesis. Multiple alternatively spliced transcript variants have been observed at this gene. [provided by RefSeq, Aug 2016]

LOC124904729 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CALM3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CALM3. . Gene score misZ 2.9788 (greater than the threshold 3.09). Trascript score misZ 3.6287 (greater than threshold 3.09). GenCC has associacion of gene with long QT syndrome, familial long QT syndrome, long QT syndrome 16, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 19-46608584-A-C is Pathogenic according to our data. Variant chr19-46608584-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 409871.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM3	NM_005184.4	c.281A>C	p.Asp94Ala	missense_variant	4/6	ENST00000291295.14	NP_005175.2
LOC124904729	XR_007067276.1	n.485T>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM3	ENST00000291295.14	c.281A>C	p.Asp94Ala	missense_variant	4/6	1	NM_005184.4	ENSP00000291295	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

ClinVar contains an entry for this variant (Variation ID: 409871). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of CALM3-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 94 of the CALM3 protein (p.Asp94Ala). -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 25, 2018

Found in an 8-year-old female with a recent history of sudden cardiac arrest. p.Asp94Ala (D94A; c.281A>C) in exon 4 of the CALM3 gene (NM_005184.2) Chromosome position: 19:47111841 A / C Based on the information reviewed below, we classify this variant as Likely Disease Causing, concluding that there is sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk family members. This variant is novel and has not been reported in the biomedical literature. However, this gene was only recently associated with sudden cardiac arrest in infants and young children. Clinical genetic testing has been available for CALM3 for only a few years, and very few variants have been reported. Specifically, there are only 4 Likely Pathogenic or Pathogenic missense variants listed in ClinVar as of 1/25/2018. This is one of three genes that code for human calmodulin (CALM1, CALM2, and CALM3), which produce proteins with identical amino acid sequences. The vast majority of reportedly pathogenic variants in these genes, thus far, have been de novo in children with cardiac arrest. The Asp94Ala variant is de novo in our affected patient with cardiac arrest at age 8, and we consider this convincing evidence of pathogenicity. The papers to date involving CALM1-3 indicate that the pathogenic mutations are located in one of the four “EF-hands” (calcium-binding loops) in the protein, specifically at residues that interact with and bind calcium. Our patient’s variant is in calcium-binding loop III, and it modifies an Aspartic Acid that interacts directly with calcium: p.Asp94Ala. It is adjacent to other reported disease-causing variants in CALM1, CALM2, or CALM3, which all form an identical calmodulin protein product, from the recent papers (Asp96Val, Asn98Ser, Asn98Ile), some of which have been reported more than once (references: Nyegaard et al. 2012; Crotti et al. 2013; Makita et al. 2014; Boczek et al. 2016). This is a nonconservative amino acid change, resulting in the replacement of a negatively-charged Aspartic Acid with a nonpolar Alanine. Aspartic Acid at this location is absolutely conserved across vertebrate species, and surrounding residues are also highly conserved. Calmodulin has a constraint metric of z = 2.92 in ExAC, indicating that missense variation is not well-tolerated (9 missense variant observed, with 52 expected). Variation at nearby residues of calmodulin has been associated with sudden cardiac arrest in infants and young children, which supports the functional importance of this region of the protein. Invitae reports that in-silico algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, although these predictions have not been confirmed by published functional studies. As of 1/25/2018, this variant is absent from the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;.;.;D;.
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.2	.;D;.;.;.;.
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Vest4		0.94
MutPred		0.73		.;Loss of stability (P = 0.0133);.;.;.;Loss of stability (P = 0.0133);
MVP		0.94
MPC		3.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502608; hg19: chr19-47111841;