NM_002335.4:c.3107G>A

Variant names:

• chr11-68423568-G-A
• rs61889560
• NM_002335.4:c.3107G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:10 O:1
• Conservation: PhyloP100: 3.48
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• bone mineral density quantitative trait locus 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• exudative vitreoretinopathy 4

  Inheritance: AD, SD, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• osteoporosis-pseudoglioma syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant osteosclerosis, Worth type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• polycystic liver disease 4 with or without kidney cysts

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant osteopetrosis 1

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• exudative vitreoretinopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyperostosis corticalis generalisata

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteosclerosis-developmental delay-craniosynostosis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• polycystic liver disease 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 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, 10 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, autosomal dominant osteopetrosis 1, osteoporosis-pseudoglioma syndrome, autosomal dominant osteosclerosis, Worth type, polycystic liver disease 4 with or without kidney cysts, bone mineral density quantitative trait locus 1, osteosclerosis-developmental delay-craniosynostosis syndrome, hyperostosis corticalis generalisata, exudative vitreoretinopathy, polycystic liver disease 1, inherited retinal dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.027751774).
• BP6: Variant 11-68423568-G-A is Benign according to our data. Variant chr11-68423568-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 183255.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AD,AR,SD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.3107G>A	p.Arg1036Gln	missense	Exon 14 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.1364G>A	p.Arg455Gln	missense	Exon 14 of 23	NP_001278831.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	ENST00000294304.12	TSL:1 MANE Select	c.3107G>A	p.Arg1036Gln	missense	Exon 14 of 23	ENSP00000294304.6
	LRP5	ENST00000529993.5	TSL:1	n.*1713G>A		non_coding_transcript_exon	Exon 14 of 23	ENSP00000436652.1
	LRP5	ENST00000529993.5	TSL:1	n.*1713G>A		3_prime_UTR	Exon 14 of 23	ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152186 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.00249 AC: 627 AN: 251472 AF XY: 0.00237

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 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.: 21 Cov.: 33 AF XY: 0.00437 AC XY: 3178 AN XY: 727240

African (AFR) AF: 0.00140 AC: 47 AN: 33478

American (AMR) AF: 0.00203 AC: 91 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

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

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86258

European-Finnish (FIN) AF: 0.00144 AC: 77 AN: 53418

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.00544 AC: 6049 AN: 1111996

Other (OTH) AF: 0.00465 AC: 281 AN: 60392

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74466

African (AFR) AF: 0.00140 AC: 58 AN: 41564

American (AMR) AF: 0.00183 AC: 28 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00377 Hom.: 3

Bravo AF: 0.00301

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:7

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.

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)

Sep 05, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRP5: BP4, BS2

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Uncertain:1 Benign: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

Nov 16, 2017

Eurofins Ntd Llc (ga)

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	0.010	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.5
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.68
Sift	Benign	0.044	D
Sift4G	Uncertain	0.052	T
Polyphen		0.66	P
Vest4		0.50
MVP		0.97
MPC		0.67
ClinPred		0.035	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.73
Mutation Taster		=30/70	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: rs61889560; hg19: chr11-68191036; COSMIC: COSV53717462;