rs730882092

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_000527.5(LDLR):c.892A>G(p.Met298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M298I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: -0.428

Publications

4 publications found

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

BP4

Computational evidence support a benign effect (MetaRNN=0.12611541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.892A>G	p.Met298Val	missense_variant	Exon 6 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.892A>G	p.Met298Val	missense_variant	Exon 6 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251406

AF XY:

0.0000221

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458608

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39522

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1109828

Other (OTH)

AF:

0.00

AC:

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Apr 03, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M298V variant (also known as c.892A>G), located in coding exon 6 of the LDLR gene, results from an A to G substitution at nucleotide position 892. The methionine at codon 298 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in compound heterozygotes from familial hypercholesterolemia (FH) cohorts; however, phase was not determined and clinical details were limited (Rubba P et al. Eur J Prev Cardiol, 2017 Jul;24:1051-1059; Martín-Campos JM et al. J Clin Lipidol, 2018 Sep;12:1452-1462). In an exome study, this alteration was described in three individuals with reportedly normal LDL-C levels and no history of myocardial infarction; these investigators also conducted in vitro studies, which did not suggest a significant impact on LDL uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Other:1

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance:not provided

Review Status:no classification provided

Collection Method:in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.14

CADD

Benign

2.0

(source)

DANN

Benign

0.48

DEOGEN2

Uncertain

0.58

D;.;.;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.42

T;T;T;T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.13

T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

-1.1

N;.;.;.;.;N

PhyloP100

-0.43

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.86

N;N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.067

T;T;D;T;T;T

Sift4G

Benign

0.16

T;T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.;.

Vest4

0.15

MutPred

0.51

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;.;.;Loss of loop (P = 0.1242);

MVP

0.94

MPC

0.21

ClinPred

0.024

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.86

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over