NM_000527.5:c.2389G>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_000527.5(LDLR):c.2389G>T(p.Val797Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V797M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 2.41

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant 19-11128085-G-T is Pathogenic according to our data. Variant chr19-11128085-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11128085-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.2389G>T	p.Val797Leu	missense_variant, splice_region_variant	Exon 16 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.2389G>T	p.Val797Leu	missense_variant, splice_region_variant	Exon 16 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727120

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3Uncertain:1

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

0/150 non-FH alleles -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Cardiovascular phenotype

Pathogenic:1

Feb 08, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2389G>T pathogenic mutation (also known as p.V797L), located in coding exon 16 of the LDLR gene, results from a G to T substitution at nucleotide position 2389. The amino acid change results in valine to leucine at codon 797, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 16, and has been revealed to cause exon 16 skipping which is expected to cause an in-frame deletion of 26 amino acids (p.A771_I796del) in the extracellular and the trans-membrane domain of the LDLR protein (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). This alteration (described as p.V776L) was detected in an individual with familial hypercholesterolemia (FH) and in his two affected children, while it was absent in his unaffected child (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). The alteration has also been reported in FH cohorts, but clinical details were limited (Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). In addition, alterations affecting this splice junction, including one at the same nucleotide (c.2389G>A), have been reported in association with FH (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Hegele RA. Genome, 2006 Nov;49:1343-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia

Pathogenic:1

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 797 of the LDLR protein (p.Val797Leu). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10735632, 19411563). It has also been observed to segregate with disease in related individuals. This variant is also known as V776L. ClinVar contains an entry for this variant (Variation ID: 252298). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 19411563). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.81

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.28

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.30

PROVEAN

Benign

-0.14

Sift

Benign

0.053

Sift4G

Benign

0.13

Vest4

0.13

MVP

0.98

ClinPred

0.19

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.46

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over