rs201185673

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014476.6(PDLIM3):c.683C>T(p.Pro228Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,606,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PDLIM3
NM_014476.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.70

Publications

1 publications found

Variant links:

Genes affected

PDLIM3 (HGNC:20767): (PDZ and LIM domain 3) The protein encoded by this gene contains a PDZ domain and a LIM domain, indicating that it may be involved in cytoskeletal assembly. In support of this, the encoded protein has been shown to bind the spectrin-like repeats of alpha-actinin-2 and to colocalize with alpha-actinin-2 at the Z lines of skeletal muscle. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Aberrant alternative splicing of this gene may play a role in myotonic dystrophy. [provided by RefSeq, Apr 2012]

PDLIM3 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PDLIM3 links:

ENSG00000249679 (HGNC:):

ENSG00000249679 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012221932).

BP6

Variant 4-185506632-G-A is Benign according to our data. Variant chr4-185506632-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520259.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM3	NM_014476.6 link	c.683C>T	p.Pro228Leu	missense_variant	Exon 6 of 8	ENST00000284767.12	NP_055291.2	Q53GG5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDLIM3	ENST00000284767.12 link	c.683C>T	p.Pro228Leu	missense_variant	Exon 6 of 8	5	NM_014476.6	ENSP00000284767.8		Q53GG5-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000302

AC:

AN:

245010

AF XY:

0.000278

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000148

AC:

215

AN:

1454410

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

113

AN XY:

723710

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000268

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00559

AC:

146

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111900

Other (OTH)

AF:

0.000381

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.000131

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000883

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Oct 29, 2013

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P228L variant (also known as c.683C>T) is located in coding exon 6 of the PDLIM3 gene. This alteration results from a C to T substitution at nucleotide position 683. The proline at codon 228 is replaced by leucine, an amino acid with similar properties.This variant was previously reported in the SNPDatabase as rs201185673. Based on data from the NHLBI Exome Sequencing Project (ESP), the T-allele has an overall frequency of approximately 0.01% (1/13,006), having not been observed in 4406 of African American alleles, and observed in 0.01% (1/8600) of European American alleles studied. This variant was not observed in the 1000 Genomes Project.This amino acid position is not conserved on sequence alignment.This variant is predicted to be benign by PolyPhen and tolerated by SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.P228L remains unclear. -

not specified

Benign:1

Mar 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy

Benign:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 10, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.16

T;.;.;.

Eigen

Benign

-0.021

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;D;T;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;.;.

PhyloP100

3.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.8

.;.;N;.

REVEL

Benign

0.067

Sift

Benign

0.39

.;.;T;.

Sift4G

Benign

0.29

.;.;T;.

Polyphen

0.027

B;.;B;.

Vest4

0.59

MVP

0.72

MPC

0.16

ClinPred

0.056

GERP RS

5.8

Varity_R

0.12

gMVP

0.28

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over