Cardiology Research and Practice

Research Article

Genetic Variants Are Not Rare in ICD Candidates with Dilated Cardiomyopathy: Time for Next-Generation Sequencing?

Table 3

Classification of genetic variants (hg 19).


Gene	Transcript	NM (NCBI)	Genomic location	Nucleotide change	Amino acid change	MAF ExAC	dbSBP	SIFT [13]	Mutation Taster [14]	Polyphen-2 [15]	ACMG/AMP final classification and criteria

TPM1	ENST00000288398	NM_000366.5	Chr15:63354830	c.758T > C^#	p.Ile253Thr	—	—	Deleterious	Disease causing	Possibly damaging	VUS (PM2, PP3)
TNNT2	ENST00000367318	NM_001001430.2	Chr1:201332477	c.517C > T	p.Arg173Trp	—	rs727503512	Deleterious	Disease causing	Probably damaging	Likely pathogenic (PS4, PP3, PP1, PP5, PP4)
MYH7	ENST00000355349	NM_000257.3	Chr14:23414039	c.5623G > T^#	p.Val1875Phe	—	—	Deleterious	Disease causing	Probably damaging	VUS (PM2, PP3)
PLN	ENST00000357525	NM_002667.3
Case 4			Chr6:118880145	c.61C > A	p.Pro21Thr	0.00005779	rs397516786	Tolerated	Disease causing	Probably damaging	VUS (PP3)
Case 5			Chr6:118558944	c.23C > T^#	p.Thr8Ile	—	—	Deleterious	Disease causing	Probably damaging	VUS (PM2)
MYBPC3	ENST00000545968	NM_000256.3	Chr11:47364805	c.1226 + 6T > C^†	—	0.00006195	rs397515892	—	—	—	VUS

ACMG/AMP: American College of Medical Genetics and Genomics/Association for Molecular Pathology [8]. MAF: minor allele frequency. Evidence for variant classification: PS, pathogenic strong; PM, pathogenic moderate; PP, pathogenic supporting; the numbering within each category does not convey any differences of weight and refer the different criteria: PS4, the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls; PP1, cosegregation with disease in multiple affected family members in a gene is definitively known to cause the disease; PP3, multiple lines of computational evidence support a deleterious effect on the gene or gene product; PP4, patient’s phenotype or family history is highly specific for a disease with a single genetic etiology; PP5, reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation; PM2, the variant is absent from (or below the expected carrier frequency if recessive) a large general population or a control cohort (>1000 individuals), and the population is race-matched to the patient harboring the identified variant. ^#Novel variant (not present in Exome Aggregation Consortium (ExAC) [16], Exome Sequencing Project (ESP) (http://evs.gs.washington.edu/EVS), 1000 Genomes (1 KG) [17], Single Nucleotide Polymorphism (dbSNP) [18], The Human Gene Mutation Database (HGMD) [19], ClinVar [20], and Leiden Open Variation Database (LOVD)) [21]. ^†This variant has probably no impact on splicing. VUS: variant of uncertain significance.