chr10-86718110-C-T

Variant names:

• chr10-86718110-C-T
• rs145983824
• NM_007078.3:c.1823C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PP3_Strong BS1_Supporting

The NM_007078.3(LDB3):​c.1823C>T​(p.Pro608Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,052 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P608P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:7
• Conservation: PhyloP100: 7.91
• Publications: 10 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):

• dilated cardiomyopathy

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: ClinGen
• myofibrillar myopathy 4

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

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_007078.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000092 (14/152184) while in subpopulation NFE AF = 0.000132 (9/68048). AF 95% confidence interval is 0.000068. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	NM_007078.3	MANE Select	c.1823C>T	p.Pro608Leu	missense	Exon 11 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1838C>T	p.Pro613Leu	missense	Exon 11 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1682C>T	p.Pro561Leu	missense	Exon 12 of 15	NP_001354995.1	A0A8I5KV04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.1823C>T	p.Pro608Leu	missense	Exon 11 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.2027C>T	p.Pro676Leu	missense	Exon 11 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1964C>T	p.Pro655Leu	missense	Exon 12 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251488 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 727232

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53410

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

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

African (AFR) AF: 0.0000724 AC: 3 AN: 41440

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000945 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	not specified (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (1)
1	-	-	Familial hypertrophic cardiomyopathy 24 (1)
-	1	-	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.97
MPC		0.77
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.47
Mutation Taster		=15/85	disease causing

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: rs145983824; hg19: chr10-88477867; COSMIC: COSV53943358; COSMIC: COSV53943358;