rs557956141

chr10-86706709-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_007078.3(LDB3):c.1075G>A(p.Asp359Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,611,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign 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. D359E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.17

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035194546).
• BP6: Variant 10-86706709-G-A is Benign according to our data. Variant chr10-86706709-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1075G>A	p.Asp359Asn	missense_variant	8/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1075G>A	p.Asp359Asn	missense_variant	8/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 25 AN: 243266 Hom.: 0 AF XY: 0.0000982 AC XY: 13 AN XY: 132394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000586

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: 0.0000277

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1459452 Hom.: 0 Cov.: 32 AF XY: 0.0000386 AC XY: 28 AN XY: 725992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000651

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.0000660 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2022

The p.D359N variant (also known as c.1075G>A), located in coding exon 7 of the LDB3 gene, results from a G to A substitution at nucleotide position 1075. The aspartic acid at codon 359 is replaced by asparagine, an amino acid with highly similar properties. This variant (also referred to as D366N) has been detected in individuals from hypertrophic cardiomyopathy and sudden death cohorts (Theis JL et al. Biochem Biophys Res Commun. 2006 Dec;351(4):896-902; Martinez-Matilla M et al. Forensic Sci Int Genet. 2019 09;42:203-212). This variant was also detected in an individual from a cohort with suspected limb-girdle muscular dystrophy who had a variant in a different gene that was thought to be causative of the reported phenotype (Kuhn M et al. J Neurol. 2016 Apr;263(4):743-50). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Myofibrillar myopathy 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2020

Identified in patients diagnosed with HCM or sudden unexpected death (Theis et al., 2006, Martinez-Matilla et al., 2019); Observed in an individual with suspected limb girdle muscular dystrophy, Paget's disease, and dementia who had a different genetic etiology for the phenotype (Kuhn et al., 2016); Identified, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx; no segregation data are available to clarify the role of this variant in disease; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #201845; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Located in an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 26886200, 17097056, 31376648) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Benign	0.82
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.14
Sift	Benign	0.31	T
Sift4G	Benign	0.59	T
Polyphen		0.33	B
Vest4		0.19
MutPred		0.21		Gain of glycosylation at P361 (P = 0.0836);
MVP		0.86
ClinPred		0.040	T
GERP RS		4.2
Varity_R		0.032

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

Publications

LitVar

Other links and lift over

dbSNP: rs557956141; hg19: chr10-88466466; COSMIC: COSV53949687;