11-68386582-C-T

Position:

• chr11-68386582-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002335.4(LRP5):​c.1282C>T​(p.Arg428Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LRP5 NM_002335.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.02

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]

ACMG classification

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 11-68386582-C-T is Pathogenic according to our data. Variant chr11-68386582-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68386582-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.1282C>T	p.Arg428Ter	stop_gained	6/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.1282C>T	p.Arg428Ter	stop_gained	6/23	1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5	c.1282C>T	p.Arg428Ter	stop_gained, NMD_transcript_variant	6/23	1		ENSP00000436652

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461572 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727130

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2022	Nonsense 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35383688, 11719191, 33707600, 16390319, 16252235) -

Osteoporosis with pseudoglioma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 16, 2001

- -

LRP5-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2023

The LRP5 c.1282C>T variant is predicted to result in premature protein termination (p.Arg428*). This variant was reported in a homozygous individual presenting with Osteoporosis-pseudoglioma syndrome (Figure 2A, Gong et al 2001. PubMed ID: 11719191). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in LRP5 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Osteoporosis;C0432252:Osteoporosis with pseudoglioma;C0432273:Worth disease;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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		2.9

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

Other links and lift over

dbSNP: rs121908661; hg19: chr11-68154050;