rs80338754

Positions:

• chr2-169140514-TG-T
• chr2-169140514-TG-TGG

Variant summary

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

The NM_004525.3(LRP2):​c.13139delC​(p.Pro4380fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRP2 NM_004525.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.10

Genes affected

LRP2 (HGNC:6694): (LDL receptor related protein 2) The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

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 2-169140514-TG-T is Pathogenic according to our data. Variant chr2-169140514-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.13139delC	p.Pro4380fs	frameshift_variant	72/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.13010delC	p.Pro4337fs	frameshift_variant	71/78		XP_011509485.1
LRP2	XM_047444340.1	c.12215delC	p.Pro4072fs	frameshift_variant	72/79		XP_047300296.1
LRP2	XM_011511184.3	c.10850delC	p.Pro3617fs	frameshift_variant	57/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.13139delC	p.Pro4380fs	frameshift_variant	72/79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1	n.4007-905delC		intron_variant				ENSP00000497617.1
LRP2	ENST00000650252.1	n.*820-7delC		splice_region_variant, intron_variant				ENSP00000496887.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438790 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716632

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: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Donnai-Barrow syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 01, 2015	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2023	This sequence change creates a premature translational stop signal (p.Pro4380Hisfs*46) in the LRP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LRP2 are known to be pathogenic (PMID: 17632512, 25682901). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LRP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 211391). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs80338754; hg19: chr2-169997024;