rs200796750

Positions:

chr10-86706683-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_007078.3(LDB3):c.1049C>T(p.Thr350Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,612,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/19 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 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.492

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 Likely_benign. Variant got -5 ACMG points.

BP6

Variant 10-86706683-C-T is Benign according to our data. Variant chr10-86706683-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222687.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}. Variant chr10-86706683-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.1049C>T	p.Thr350Ile	missense_variant	8/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.1049C>T	p.Thr350Ile	missense_variant	8/14	1	NM_007078.3	P4	O75112-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000125

AC:

AN:

247570

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

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:

0.000261

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

227

AN:

1460558

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000204

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Myofibrillar myopathy 4

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*7309C>T in the primary transcript. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 350 of the LDB3 protein (p.Thr350Ile). This variant is present in population databases (rs200796750, gnomAD 0.03%). This missense change has been observed in individual(s) with Barth syndrome (PMID: 17394203). ClinVar contains an entry for this variant (Variation ID: 222687). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2019

Reported in the literature in a patient with Barth syndrome and severe LVNC/DCM, and was also identified in this patient's sibling and father, who have prominent trabeculations but do not meet criteria for LVNC (Marziliano et al., 2007; Arbustini et al., 2016); this patient also harbors a maternally inherited frameshift variant in the TAZ gene; Reported also in association with HCM (Lopes et al., 2015); Identified both independently and in conjunction with additional cardiogenetic variants in unrelated individuals with DCM referred for genetic testing at GeneDx, but segregation data is limited or absent at this time; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 222687; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25351510, 17394203, 27561770, 23299917, 21303826) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2023

The p.T350I variant (also known as c.1049C>T), located in coding exon 7 of the LDB3 gene, results from a C to T substitution at nucleotide position 1049. The threonine at codon 350 is replaced by isoleucine, an amino acid with similar properties. This variant co-occurred with a TAZ frameshift alteration in an individual with Barth syndrome and non-compaction cardiomyopathy. The proband's healthy father and brother had the LDB3 variant and showed prominent cardiac trabeculation, and otherwise normal cardiac exam (Marziliano N et al. Am. J. Med. Genet. A, 2007 May;143A:907-15). This alteration has also been reported in a limb girdle muscular dystrophy cohort (Marziliano N et al. Am. J. Med. Genet. A, 2007 May;143A:907-15). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28). This amino acid position is not conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 19, 2015

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Nov 26, 2019

LDB3 Thr350Ile has been reported previously in 1 proband diagnosed with Barth Syndrome and left ventricular noncompaction, he was also found to be hemizygous for the TAZ Glu202Valfs variant (Marziliano N, et al., 2007). We identified this variant in a HCM proband of Eastern European descent and no family history of HCM or sudden cardiac death. The variant is present in the Genome Aggregation Database (MAF= 0.00013, http://gnomad.broadinstitute.org/), at an allele frequency which higher than expected for these disorders. Computational tools SIFT and PolyPhen2 predict this variant to have a deleterious effect, however MutationTaster predicts this variant to be a "polymorphism". In summary, based on the elevated allele frequency in the general population and limited information we classify LDB3 Thr350Ile as a variant of "uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.16

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.28

M_CAP

Benign

0.0091

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.040

REVEL

Uncertain

0.48

Sift

Benign

0.42

Sift4G

Benign

0.30

Polyphen

0.82

Vest4

0.67

MVP

0.83

ClinPred

0.058

GERP RS

3.5

Varity_R

0.054

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