NM_002335.4:c.1999G>C

Variant names:

• chr11-68406721-G-C
• rs4988321
• NM_002335.4:c.1999G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002335.4(LRP5):​c.1999G>C​(p.Val667Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V667M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP5 NM_002335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87
• Publications: 89 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
• LRP5-related exudative vitreoretinopathy

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• exudative vitreoretinopathy 4

  Inheritance: Unknown, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• autosomal dominant osteosclerosis, Worth type

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

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

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.1999G>C	p.Val667Leu	missense	Exon 9 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.256G>C	p.Val86Leu	missense	Exon 9 of 23	NP_001278831.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	ENST00000294304.12	TSL:1 MANE Select	c.1999G>C	p.Val667Leu	missense	Exon 9 of 23	ENSP00000294304.6	O75197
	LRP5	ENST00000529993.5	TSL:1	n.*605G>C		non_coding_transcript_exon	Exon 9 of 23	ENSP00000436652.1	E9PHY1
	LRP5	ENST00000529993.5	TSL:1	n.*605G>C		3_prime_UTR	Exon 9 of 23	ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.49
Sift	Benign	0.12	T
Sift4G	Benign	0.29	T
Polyphen		0.14	B
Vest4		0.62
MutPred		0.27		Gain of catalytic residue at V667 (P = 0.0579)
MVP		0.90
MPC		0.42
ClinPred		0.73	D
GERP RS		4.1
Varity_R		0.19
gMVP		0.73
Mutation Taster		=20/80	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: rs4988321; hg19: chr11-68174189;