rs142143310

Variant names:

• chr4-185506600-C-T
• rs142143310
• NM_014476.6:c.715G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014476.6(PDLIM3):​c.715G>A​(p.Asp239Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,611,612 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D239G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: PDLIM3 NM_014476.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: 1.21
• Publications: 4 publications found

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

ENSG00000249679 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004471153).
• BP6: Variant 4-185506600-C-T is Benign according to our data. Variant chr4-185506600-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201953.
• BS2: High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM3	NM_014476.6	c.715G>A	p.Asp239Asn	missense_variant	Exon 6 of 8	ENST00000284767.12	NP_055291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDLIM3	ENST00000284767.12	c.715G>A	p.Asp239Asn	missense_variant	Exon 6 of 8	5	NM_014476.6	ENSP00000284767.8

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000731 AC: 182 AN: 249114 AF XY: 0.000660

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.000103

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000332 AC: 484 AN: 1459462 Hom.: 1 Cov.: 32 AF XY: 0.000337 AC XY: 245 AN XY: 726114

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 340 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.0000392 AC: 2 AN: 51056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111970

Other (OTH) AF: 0.000977 AC: 59 AN: 60380

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74332

African (AFR) AF: 0.0000965 AC: 4 AN: 41438

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68016

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000653 Hom.: 0

Bravo AF: 0.000468

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Aug 08, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Testing for our patient was done at GeneDx. Given the lack of case data, the variant's frequency in general population databases and limited gene level evidence, we consider this variant likely benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene Level Evidence for PDLIM3 and cardiomyopathy There is limited evidence that variants in the PDLIM3 gene cause cardiomyopathy. Variants in the PDLIM3 gene have rarely been reported in patients with hypertrophic and dilated cardiomyopathy, identified through candidate gene screening of DCM and HCM patient cohorts. It has also been proposed that PDLIM3 splicing mutations may play a role in myotonic dystrophy. Variant level evidence There are no published reports of this variant in any cases of cardiomyopathy, arrhythmia, or sudden death. There is no case data. In silico analysis do not agree on the predicted effect of the variant. The aspartic acid at codon 239 is not well conserved across species, suggesting variation at this position may be tolerated. There are no other variants reported as pathogenic in ClinVar. The variant is present in the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/), which currently includes variant calls on >66,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant was observed in 49 of 33,236 individuals of European descent (MAF=0.07%), 5 of 5780 individuals of Latino descent (MAF=0.04%), 2 of 5170 individuals of African descent (MAF=0.02%), and 1 of 4303 individuals of East Asian descent (MAF=0.01%). 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 variant was reported online in 178 of 140,188 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 135 of 5081 individuals of Ashkenazi Jewish descent (MAF=1.3%). Of note, one of the Ashkenazi Jewish individuals was homozygous for this variant. The variant was also present in 6 of 9466 individuals of East Asian descent (MAF=0.03%), 10 of 19236 individuals of Latino descent (MAF=0.02%), 12 of 63,381 individuals of European descent (MAF=0.01%), and 2 of 12,931 individuals of African descent (MAF=0.01%). 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. -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PDLIM3: BP4, BS1 -

not specified Uncertain:1

Mar 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Asp239Asn var iant in PDLIM3 has not been previously reported in individuals with cardiomyopat hy, but has been identified 0.07% (49/66472) of European chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14214331 0). Aspartic acid (Asp) at position 239 is not conserved in evolution and 3 mamm als (prairie vole and 2 bats) have an asparagine (Asn) at this position, suggest ing that this change may be tolerated. In summary, while the clinical significan ce of the p.Asp239Asn variant is uncertain, the presence of the variant amino ac id in other mammals combined with the frequency in the general population sugges ts that it is more likely to be benign. -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Benign:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cardiomyopathy Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.;.
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.4	.;.;N;.
REVEL	Benign	0.055
Sift	Uncertain	0.0030	.;.;D;.
Sift4G	Uncertain	0.0070	.;.;D;.
Polyphen		0.0010	B;.;B;.
Vest4		0.14
MVP		0.62
MPC		0.15
ClinPred		0.021	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.37
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs142143310; hg19: chr4-186427754;