rs61889560

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBS1BS2

The NM_002335.4(LRP5):c.3107G>A(p.Arg1036Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00437 in 1,614,172 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts 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. R1036L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 21 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:10O:1

Conservation

PhyloP100: 3.48

Variant links:

Genes affected

LRP5 (HGNC:6697): (LDL receptor related protein 5) This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

LRP5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_002335.4

PP2

Missense variant in the LRP5 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 71 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 1.6684 (below the threshold of 3.09). Trascript score misZ: 3.6986 (above the threshold of 3.09). GenCC associations: The gene is linked to exudative vitreoretinopathy 4, polycystic liver disease 4 with or without kidney cysts, polycystic liver disease 1, exudative vitreoretinopathy, osteosclerosis-developmental delay-craniosynostosis syndrome, bone mineral density quantitative trait locus 1, autosomal dominant osteopetrosis 1, hyperostosis corticalis generalisata, osteoporosis-pseudoglioma syndrome, autosomal dominant osteosclerosis, Worth type, inherited retinal dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.027751774).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00254 (387/152304) while in subpopulation NFE AF= 0.00419 (285/68022). AF 95% confidence interval is 0.00379. There are 1 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.3107G>A	p.Arg1036Gln	missense_variant	Exon 14 of 23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP5	ENST00000294304.12 link	c.3107G>A	p.Arg1036Gln	missense_variant	Exon 14 of 23	1	NM_002335.4	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5 link	n.*1713G>A		non_coding_transcript_exon_variant	Exon 14 of 23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5 link	n.*1713G>A		3_prime_UTR_variant	Exon 14 of 23	1		ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.00254

AC:

387

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00419

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00249

AC:

627

AN:

251472

Hom.:

AF XY:

0.00237

AC XY:

322

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00456

AC:

6664

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3178

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000881

Gnomad4 FIN exome

AF:

0.00144

Gnomad4 NFE exome

AF:

0.00544

Gnomad4 OTH exome

AF:

0.00465

GnomAD4 genome

AF:

0.00254

AC:

387

AN:

152304

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00419

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00396

Hom.:

Bravo

AF:

0.00301

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00249

AC:

302

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:7

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25920554, 22487062, 27884173, 16390319, 15824851, 19673927, 28378289, 25390515, 31039433, 30652979, 33118644) -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LRP5 c.3107G>A; p.Arg1036Gln variant (rs61889560) is reported in the literature in individuals affected with osteoporosis (Caetano da Silva 2021, Hartikka 2005, Sturznickel 2021) or polycystic kidney disease (Cnossen 2016), but did not segregate with disease in some families. This variant is also reported in ClinVar (Variation ID: 183255), and is found in the general population with an overall allele frequency of 0.24% (692/282864 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.683). In vitro functional analyses demonstrate reduced Wnt signaling, but no effect on expression of downstream genes (Cnossen 2016, Korvala 2012). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Caetano da Silva C et al. More severe phenotype of early-onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A. Mol Genet Genomic Med. 2021 Jun;9(6):e1681. PMID: 33939331. Cnossen WR et al. LRP5 variants may contribute to ADPKD. Eur J Hum Genet. 2016 Feb;24(2):237-42. PMID: 25920554. Hartikka H et al. Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res. 2005 May;20(5):783-9. PMID: 15824851. Korvala J et al. Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med Genet. 2012 Apr 10;13:26. PMID: 22487062. Sturznickel J et al. Clinical Phenotype and Relevance of LRP5 and LRP6 Variants in Patients With Early-Onset Osteoporosis (EOOP). J Bone Miner Res. 2021 Feb;36(2):271-282. PMID: 33118644. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRP5: BP4 -

not specified

Uncertain:1Benign:2

Mar 23, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta

Uncertain:1

Jun 24, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Postmenopausal osteoporosis;C0432252:Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843323:Van Buchem disease type 2;C1843330:Autosomal dominant osteopetrosis 1;C1851402:Exudative vitreoretinopathy 1;C1866079:Bone mineral density quantitative trait locus 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant polycystic kidney disease

Uncertain:1

Sep 01, 2021

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Autosomal dominant osteopetrosis 1

Uncertain:1

Apr 06, 2020

Genetics Department, Polish Mother's Memorial Hospital Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

LRP5-related disorder

Benign:1

May 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Polycystic kidney disease, adult type

Other:1

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Significance: not provided

Review Status: no classification provided

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.028

MetaSVM

Uncertain

0.010

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.68

Sift

Benign

0.044

Sift4G

Uncertain

0.052

Polyphen

0.66

Vest4

0.50

MVP

0.97

MPC

0.67

ClinPred

0.035

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.73

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over