NM_007078.3:c.1799G>C

Variant names:

• chr10-86718086-G-C
• rs747523570
• NM_007078.3:c.1799G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_007078.3(LDB3):​c.1799G>C​(p.Arg600Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R600Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.03
• Publications: 3 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• PP5: Variant 10-86718086-G-C is Pathogenic according to our data. Variant chr10-86718086-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191006.

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.1799G>C	p.Arg600Pro	missense	Exon 11 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1814G>C	p.Arg605Pro	missense	Exon 11 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1658G>C	p.Arg553Pro	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.1799G>C	p.Arg600Pro	missense	Exon 11 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.2003G>C	p.Arg668Pro	missense	Exon 11 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1940G>C	p.Arg647Pro	missense	Exon 12 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Myofibrillar myopathy 4 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.45	N
PhyloP100		5.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.61
Sift	Benign	0.40	T
Sift4G	Benign	0.13	T
Polyphen		0.16	B
Vest4		0.82
MutPred		0.51		Gain of catalytic residue at R600 (P = 0.0795)
MVP		0.94
MPC		0.93
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.71
gMVP		0.70
Mutation Taster		=53/47	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs747523570; hg19: chr10-88477843;