rs886043590

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_002335.4(LRP5):c.2737dupT(p.Cys913LeufsTer73) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,612,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

LRP5
NM_002335.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.47

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-68413921-G-GT is Pathogenic according to our data. Variant chr11-68413921-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 287187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.2737dupT	p.Cys913LeufsTer73	frameshift_variant	Exon 12 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.2737dupT	p.Cys913LeufsTer73	frameshift_variant	Exon 12 of 23	1	NM_002335.4	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5 link	n.*1343dupT		non_coding_transcript_exon_variant	Exon 12 of 23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5 link	n.*1343dupT		3_prime_UTR_variant	Exon 12 of 23	1		ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000401

AC:

AN:

249404

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1459794

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726320

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000378

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys913Leufs*73) in the LRP5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LRP5 are known to be pathogenic (PMID: 11719191, 16252235, 25711638). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal dominant osteoporosis with familial exudative vitreoretinopathy and autosomal recessive osteoporosis pseudoglioma (PMID: 16252235, 25711638). ClinVar contains an entry for this variant (Variation ID: 287187). For these reasons, this variant has been classified as Pathogenic. -

Apr 27, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported with a second pathogenic variant in a patient with pseudoglioma; however phase of the two variants was not determined in this study (Ai et al., 2005); Has also been reported as a single heterozygous variant in a patient with recurrent fractures, and in a second patient with a diagnosis of FEVR (Bardai et al., 2017; Salvo et al., 2015); Published functional studies suggest a damaging effect with this variant resulting in a protein with lower activity compared to wild-type protein (Korvala et al., 2012); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28378289, 16252235, 22487062, 25711638, 35328049, 35753512) -

Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1866079:Bone mineral density quantitative trait locus 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts

Pathogenic:1

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteoporosis with pseudoglioma

Pathogenic:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with exudative vitreoretinopathy 4 (FEVR; MIM#601813) and osteoporosis-pseudoglioma syndrome (OPPG; MIM#259770); and autosomal dominant osteopetrosis (MIM#607634), respectively (PMID: 31827910, 23744590). (I) 0108 - This gene is associated with both recessive and dominant disease. Exudative vitreoretinopathy 4 (MIM#601813) can be both autosomal dominant or recessive and is considered to be part of the spectrum of autosomal recessive osteoporosis-pseudoglioma syndrome (MIM#259770). There is currently no clear genotype-phenotype correlation distinguishing these two conditions. Instead, the functional severity of the variant determines the phenotypic consequences (PMID: 31827910). Missense variants clustered within the first b-propeller extracellular domain are associated with autosomal dominant osteopetrosis (MIM#607634; PMID: 23744590). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported for gain of function variants (PMID 23744590) and FEVR (PMID: 25323851). Patients may appear asymptomatic for osteoporosis (PMID: 15824851). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for the condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with FEVR, OPPG, and osteoporosis in the literature (PMIDs: 16252235, 25711638, 35328049, 15824851). (SP) 1206 - This variant has been shown to be paternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Exudative vitreoretinopathy 4

Pathogenic:1

Oct 18, 2018

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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