NM_007078.3:c.2016C>T

Variant names:

• chr10-86726174-C-T
• rs45578640
• NM_007078.3:c.2016C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007078.3(LDB3):​c.2016C>T​(p.Cys672Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,613,954 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (26 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.911
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000272631 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-86726174-C-T is Benign according to our data. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86726174-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.911 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (417/152268) while in subpopulation NFE AF = 0.00501 (341/68012). AF 95% confidence interval is 0.00457. There are 1 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.2016C>T	p.Cys672Cys	synonymous_variant	Exon 13 of 14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.2016C>T	p.Cys672Cys	synonymous_variant	Exon 13 of 14	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00248 AC: 623 AN: 251462 AF XY: 0.00224

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00466 AC: 6818 AN: 1461686 Hom.: 26 Cov.: 31 AF XY: 0.00451 AC XY: 3279 AN XY: 727142

African (AFR) AF: 0.000687 AC: 23 AN: 33472

American (AMR) AF: 0.000917 AC: 41 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

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

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53418

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5668

European-Non Finnish (NFE) AF: 0.00585 AC: 6505 AN: 1111938

Other (OTH) AF: 0.00306 AC: 185 AN: 60384

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74446

African (AFR) AF: 0.000986 AC: 41 AN: 41562

American (AMR) AF: 0.00163 AC: 25 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00501 AC: 341 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00405 Hom.: 1

Bravo AF: 0.00262

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 09, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDB3: BP4, BP7, BS2 -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:5

Jul 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cys672Cys in exon 15 of the LDB3 gene: This variant does not not alter an amino acid residue and is not located near a splice junction. Although some base chang es that do not result in amino acid changes can be associated with disease, this variant occurs in ~1% of the general population; rs45578640) and is therefore m ost likely benign. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Myofibrillar myopathy 4 Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LDB3-related disorder Benign:1

Aug 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

May 04, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.56
DANN	Benign	0.57
PhyloP100		-0.91
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs45578640; hg19: chr10-88485931;