rs121908334

Positions:

chr10-86687218-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001368067.1(LDB3):c.494C>T(p.Ala165Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LDB3
NM_001368067.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

LDB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.766

PP5

Variant 10-86687218-C-T is Pathogenic according to our data. Variant chr10-86687218-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86687218-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_001368067.1 linkuse as main transcript	c.494C>T	p.Ala165Val	missense_variant	6/9	ENST00000263066.11	NP_001354996.1
LDB3	NM_007078.3 linkuse as main transcript	c.690-4678C>T		intron_variant		ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000263066.11 linkuse as main transcript	c.494C>T	p.Ala165Val	missense_variant	6/9	1	NM_001368067.1	ENSP00000263066		O75112-6
LDB3	ENST00000361373.9 linkuse as main transcript	c.690-4678C>T		intron_variant		1	NM_007078.3	ENSP00000355296	P4	O75112-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249596

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135402

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	LDB3: PM2, PP1:Moderate, PS3:Moderate, PS4:Moderate, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2022	Published functional studies demonstrate a damaging effect: Z-disc disruption and F-actin accumulation in mouse skeletal muscle, and disruption in the actin cytoskeleton in muscle cells (Lin et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28269794, 19377068, 27546599, 27618136, 25208129, 27638134, 18765652, 15668942, 33742095, 31791368, 21676617, 32419263, 31589614, 17337483, 24668811) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 11, 2022	- -

Myofibrillar myopathy 4

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 165 of the LDB3 protein (p.Ala165Val). This variant is present in population databases (rs121908334, gnomAD 0.0009%). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15668942, 25208129). ClinVar contains an entry for this variant (Variation ID: 4728). 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 tolerated. Experimental studies have shown that this missense change affects LDB3 function (PMID: 24647531, 24668811). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 07, 2021	The LDB3 c.494C>T (p.Ala165Val) variant, also referred to as c.690-4678C>T, is a missense variant that has been reported in at least seven unrelated individuals with myofibrillar myopathy presenting with progressive muscle weakness, mainly distally, and myopathic motor unit potentials noted through electromyography. Muscle atrophy, tripping episodes, walking difficulty, peripheral neuropathy, decreased reflexes in the legs, tingling and numbness in the feet, and ankle movement problems were also noted in some individuals (Selcen and Engler 2005; Griggs et al. 2007; Fischer et al. 2008; Semmler et al. 2014). Only one individual had cardiac problems presenting as prolonged QT (Selec and Engler 2005). The p.Ala165Val variant segregated with disease in a large pedigree where six affected individuals carried the variant. Three additional family members who carried the variant were asymptomatic at the time of the study, but they ranged in age from 39-49 years (Griggs et al. 2007). In functional studies using a mouse model or cells derived from mice, the phenotype observed in humans was recapitulated when the p.Ala165Val variant was present in a heterozygous state. This included presence of muscle weakness, characteristic muscle fiber structural abnormalities, protein aggregation patterns, and Z-disc disruption generally observed in myofibrillar myopathy (Lin et al. 2014; Pathak et al. 2014). The p.Ala165Val variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the p.Ala165Val variant is classified as pathogenic for myofibrillar myopathy. -

Dilated cardiomyopathy 1C

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Neuromuscular disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 21, 2018

The p.Ala165Val variant in LDB3 has been reported in at least 6 individuals with myofibrillar myopathy and segregated with disease in 9 affected individuals fro m 1 family (Selcen 2005, Griggs 2007, Fischer 2008, Vincent 2016, LMM data). It has also been identified in 1/113280 of European chromosomes by gnomAD (http://g nomad.broadinstitute.org) and reported in ClinVar (Variant ID #4728). An in vitr o function study showed that this variant disrupted Ankrd2 binding (Martinelli 2 014) and a study of mouse myoblasts transfected with the p.Ala165Val mutation sh owed a disrution of Z-disc structure and an accumulation of F-actin (Lin 2014). In summary, this variant meets criteria to be classified as pathogenic for autos omal dominant myofibrillar myopathy. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 24, 2024

The c.690-4678C>T variant in LDB3 (also known as c.494C>T, p.Ala165Val with the alternate transcripts) is highly conserved. It was identified in 1/249596 (0.0004%) of alleles tested from presumed healthy individuals in the Genome Aggregation Database (gnomAD), and is considered to be a rare variant. It has been previously reported in multiple apparently unrelated individuals and families with myofibrillar myopathy, segregated with the disease, and has been reported to be a founder mutation (PMID; 15668942, 17337483, 25208129, and others). The majority of these affected individuals were not reported to have cardiomyopathy as a presenting or significant feature (reported using the alternate gene name ZASP, PMID 15668942, 17337483, 18765652, 27618136, doi: 10.17795/gct.34601, and others). Functional studies have shown conflicting results: one reported that this variant did not impact the binding between LDB3 and phosphoglucomutase 1, which is suspected to be the mechanism of development of DCM (PMID 19377068), and others showed that this variant disrupted the actin cytoskeleton of muscle cells, as well as the Ankrd2 binding (which creates the link between the sarcomere and the nucleus in skeletal muscle) (PMID 24668811, PMID 24647531). Further, heterozygous knock-in mice develop are found to develop myofibrillar myopathy, however, the cardiac muscle fibers of these mice showed normal histology (PMID 33742095). The p.Ala165 variant is present in exon 6 of alternate transcripts for LDB3; immunostaining of skeletal and cardiac muscle in mice with a knockout-validated LDB3 exon 6 antibody detected LDB3 in the skeletal muscle but not the cardiac muscle, suggesting that isoforms containing exon 6 are not the predominant isoforms expressed in the cardiac muscle (PMID 33742095). In silico splicing analyses do not predict this variant to have a significant effect on splicing. However, this prediction has not been confirmed by RNA functional studies. This variant is listed in ClinVar (VCV000004728). Based on the above evidence, we classify this variant as likely pathogenic for myofibrillar myopathy, which, in rare cases, could also produce cardiomyopathy. -

Myofibrillar myopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Aug 16, 2016

- -

LDB3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The LDB3 c.494C>T variant is predicted to result in the amino acid substitution p.Ala165Val. This variant has been reported in individuals with myofibrillar myopathy and shown to segregate with disease in families (see, for example, Selcen and Engel. 2005. PubMed ID: 15668942; Griggs et al. 2007. PubMed ID: 17337483; Semmler et al. 2014. PubMed ID: 25208129). In vitro and in vivo experimental studies suggest this variant impacts protein function (Lin et al. 2014. PubMed ID: 24668811; Martinelli et al. 2014. PubMed ID: 24647531; Pathak et al. 2021. PubMed ID: 33742095). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in a large population database. This variant is interpreted as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.690-4678C>T intronic pathogenic mutation results from a C to T substitution 4678 nucleotides upstream from coding exon 5 in the LDB3 gene. This alteration, also known as c.494C>T p.A165V in isoform NM_001080116, has been detected in multiple individuals with myofibrillar myopathy and has been reported to segregate with disease (Selcen D et al. Ann. Neurol., 2005 Feb;57:269-76; Griggs R et al. Brain, 2007 Jun;130:1477-84; Olivé M et al. Neuromuscul. Disord., 2011 Aug;21:533-42; Semmler AL et al. Orphanet J Rare Dis, 2014 Aug;9:121; Vincent AE et al. Neuromuscul. Disord., 2016 10;26:691-701). Haplotype analysis has demonstrated that this variant is a European founder mutation (Griggs R et al. Brain, 2007 Jun;130:1477-84). Functional analyses indicate that this alteration may impact protein function, but the physiological relevance of the observed impacts is unclear (Lin X et al. J. Biol. Chem., 2014 May;289:13615-26). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.77

D;D;D;D;D

MetaSVM

Uncertain

0.49

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A

PROVEAN

Benign

-1.6

N;.;N;N;N

REVEL

Pathogenic

0.78

Sift

Benign

0.35

T;.;T;T;D

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.72, 1.0, 1.0

.;.;P;D;D

Vest4

0.91

MutPred

0.51

.;.;Loss of catalytic residue at M160 (P = 0.0532);.;Loss of catalytic residue at M160 (P = 0.0532);

MVP

0.89

MPC

0.76

ClinPred

0.91

GERP RS

5.1

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over