rs397517217

Variant names:

• chr10-86716681-C-G
• rs397517217
• NM_007078.3:c.1586C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-86716681-C-G
• chr10-86716681-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007078.3(LDB3):​c.1586C>G​(p.Pro529Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20497382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.1586C>G	p.Pro529Arg	missense_variant	Exon 10 of 14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.1586C>G	p.Pro529Arg	missense_variant	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461696 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Pro529Arg varia nt (LDB3) has not been reported in the literature nor previously identified by o ur laboratory. Proline (Pro) at position 529 is not conserved in mammals or lowe r species, increasing the likelihood that a change would be tolerated. Computati onal tools are mixed in their prediction on the impact to the protein (AlignGVGD = benign, PolyPhen2 & SIFT = pathogenic), though the accuracy of these tools is unknown. The lack of conservation of this residue suggests that the Pro529Arg v ariant may be benign, but additional information is needed to fully assess its c linical significance. -

Cardiovascular phenotype Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1586C>G (p.P529R) alteration is located in exon 9 (coding exon 9) of the LDB3 gene. This alteration results from a C to G substitution at nucleotide position 1586, causing the proline (P) at amino acid position 529 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.85	T;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.1	.;.;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D;.;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D;.;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.99, 0.018	.;.;D;B
Vest4		0.13
MutPred		0.35		.;.;Gain of MoRF binding (P = 0.0021);.;
MVP		0.77
MPC		0.23
ClinPred		0.35	T
GERP RS		4.8
Varity_R		0.090
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs397517217; hg19: chr10-88476438;