rs142143310

Positions:

• chr4-185506600-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

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. 13/21 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

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 201953.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDLIM3	NM_014476.6	c.715G>A	p.Asp239Asn	missense_variant	6/8	ENST00000284767.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDLIM3	ENST00000284767.12	c.715G>A	p.Asp239Asn	missense_variant	6/8	5	NM_014476.6	A1
	ENST00000671042.1	n.617C>T		non_coding_transcript_exon_variant	4/4

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

GnomAD3 exomes AF: 0.000731 AC: 182 AN: 249114 Hom.: 1 AF XY: 0.000660 AC XY: 89 AN XY: 134802

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000392

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.000977

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

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000622 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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PDLIM3: BP4, BS1 -
Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 18, 2017	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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 11, 2015

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

- -

Familial cardiomyopathy Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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;.;.;.
MutationTaster	Benign	0.93	D;D;D
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

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

LitVar

Other links and lift over

dbSNP: rs142143310; hg19: chr4-186427754;