rs143812960
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_014476.6(PDLIM3):c.896G>A(p.Ser299Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,612,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S299R) has been classified as Uncertain significance.
Frequency
Consequence
NM_014476.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDLIM3 | NM_014476.6 | c.896G>A | p.Ser299Asn | missense_variant | 7/8 | ENST00000284767.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDLIM3 | ENST00000284767.12 | c.896G>A | p.Ser299Asn | missense_variant | 7/8 | 5 | NM_014476.6 | A1 | |
ENST00000671042.1 | n.518-2017C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251370Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135872
GnomAD4 exome AF: 0.000118 AC: 172AN: 1460248Hom.: 0 Cov.: 30 AF XY: 0.000120 AC XY: 87AN XY: 726602
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74512
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 01, 2016 | PDLIM3 p.Ser299Asn This variant is located in coding exon 7 of the PDLIM3 gene. The serine at codon 299 is replaced by asparagine, an amino acid with highly similar properties. This variant has not been reported in assocation with cardiomyopathy. We have seen the variant in one adult with unexplained cardiac arrest and mild biventricular systolic dysfunction In silico analysis with PolyPhen-2 predicts the variant to be benign. The serine at codon 299 is not well conserved across species, with asparagine as the reference amino acid in 8 species. The variant was reported online in 12 of 60312 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Aug 1 2016). Specifically, the variant was observed in 11 of 33191 Europeans (AF 0.0001657). 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. Note that in the 1000 Genomes Project (included in ExAC, above), the A-allele has an overall frequency of 0.51% (1/1,092), having been observed in 0.51% (1/98) of Tuscan individuals studies. Please note, the patient's ancestry is self-reported as Italian. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2023 | Reported in a cohort of patients with restrictive cardiomyopathy and predicted to be tolerated, no patient specific details provided (Tarnovskaya et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 28831623) - |
Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2023 | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 299 of the PDLIM3 protein (p.Ser299Asn). This variant is present in population databases (rs143812960, 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: 201948). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PDLIM3 protein function with a negative predictive value of 80%. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 04, 2013 | The p.S299N variant (also known as c.896G>A) is located in coding exon 7 of the PDLIM3gene. This alteration results from a G to A substitution at nucleotide position 896. The serine at codon 299 is replaced by asparagine, an amino acid with highly similar properties. This variant was previously reported in dbSNP asrs143812960. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.02% (3/13006), having been observed in 0.03% (3/8600) of European American alleles, and not observed in 4406 of African American alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.51% (1/2184), having been observed in 0.51% (1/196) of Tuscan alleles studied. Based on protein sequence alignment, thisamino acid position is not well conserved in available vertebrate species with asparagine as the reference amino acid in 8 species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear​. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at