1-53262190-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004631.5(LRP8):c.1792T>G(p.Leu598Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRP8 NM_004631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

Genes affected

LRP8 (HGNC:6700): (LDL receptor related protein 8) This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

LOC105378728 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP8	NM_004631.5	c.1792T>G	p.Leu598Val	missense_variant	12/19	ENST00000306052.12
LOC105378728	XR_947355.3	n.4350-3562A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP8	ENST00000306052.12	c.1792T>G	p.Leu598Val	missense_variant	12/19	1	NM_004631.5	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.1792T>G (p.L598V) alteration is located in exon 12 (coding exon 12) of the LRP8 gene. This alteration results from a T to G substitution at nucleotide position 1792, causing the leucine (L) at amino acid position 598 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.8	L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.20	T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.79
MVP		0.98
MPC		1.2
ClinPred		0.96	D
GERP RS		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.73

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: rs372186863; hg19: chr1-53727862;