chr19-11107464-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.890A>G (p.Asn297Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404080953/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 9.21

Publications

0 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 2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	NM_000527.5	MANE Select	c.890A>G	p.Asn297Ser	missense	Exon 6 of 18	NP_000518.1
LDLR	NM_001195798.2		c.890A>G	p.Asn297Ser	missense	Exon 6 of 18	NP_001182727.1
LDLR	NM_001195799.2		c.767A>G	p.Asn256Ser	missense	Exon 5 of 17	NP_001182728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.890A>G	p.Asn297Ser	missense	Exon 6 of 18	ENSP00000454071.1
LDLR	ENST00000252444.10	TSL:1	c.1148A>G	p.Asn383Ser	missense	Exon 6 of 18	ENSP00000252444.6
LDLR	ENST00000558013.5	TSL:1	c.890A>G	p.Asn297Ser	missense	Exon 6 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:2

Feb 14, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.890A>G (p.Asn297Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.0

PhyloP100

9.2

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.012

Polyphen

0.52

Vest4

0.33

MutPred

0.78

Gain of ubiquitination at K294 (P = 0.0837)

MVP

1.0

MPC

0.24

ClinPred

0.96

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.87

Mutation Taster

=31/69

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over