4-185502307-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014476.6(PDLIM3):āc.1082A>Gā(p.Tyr361Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_014476.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251490Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461890Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:2
p.Tyr361Cys (TAT>TGT): c.1082 A>G in exon 8 of the PDLIM3 gene (NM_014476.5). A variant of unknown significance has been identified in the PDLIM3 gene. The Y361C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Y361C variant was not observed in approximately 6500 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 Y361C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Although a missense mutation in a nearby residue (E106A) has been reported in association with HCM (Bagnall RD et al., 2010), there was poor segregation data for this variant which is also predicted to be benign by in silico algorithms. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). -
The p.Tyr361Cys variant in PDLIM3 has not been previously reported in the literature in individuals with cardiomyopathy but has been reported by other clinical laboratories in ClinVar (Variation ID: 201955). It has also been identified in 0.02% (4/18394) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: none. -
Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Uncertain:1
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 361 of the PDLIM3 protein (p.Tyr361Cys). This variant is present in population databases (rs779267023, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PDLIM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 201955). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at