rs750518671

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The ENST00000558518.6(LDLR):c.2389G>A(p.Val797Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V797L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19U:3

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in ENST00000558518.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP5

Variant 19-11128085-G-A is Pathogenic according to our data. Variant chr19-11128085-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11128085-G-A is described in Lovd as [Pathogenic]. Variant chr19-11128085-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2389G>A	p.Val797Met	missense_variant, splice_region_variant	16/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2389G>A	p.Val797Met	missense_variant, splice_region_variant	16/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251360

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:11Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 25, 2024	This missense variant changes the last nucleotide c.G of exon 16 of the LDLR gene and is predicted to impair RNA splicing at the intron 16 splice donor site. This variant is also known as p.Val776Met in the mature protein. RNA studies from carrier individuals have shown that this variant causes skipping of exon 16 (PMID: 34497632), and leads to absence of wild-type transcript (PMID: 9763532). In vitro functional studies have shown that this variant causes a reduction in LDLR internalization and expression at the cellular membrane (PMID: 34497632). This variant has been reported in over 20 heterozygous individuals affected with familial hypercholesterolemia (PMID: 7649549, 9763532, 18718593, 19446849, 20145306, 22698793, 22859806, 23375686, 27816806, 33418990, 33794673, 34497632). This variant has also been observed in homozygous state in two individuals affected with severe homozygous familial hypercholesterolemia (PMID: 33093846, 36229885). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 7649549, 34497632). This variant has been identified in 2/251360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2389G>T (p.Val797Leu), is considered to be disease-causing (ClinVar variation ID: 252298), suggesting that valine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	Affects splicing, IVS16 ds -1 G>A. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Apr 12, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Uncertain significance, flagged submission	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/150 non-FH alleles; 0/100 healthy control individuals; 0/60 healthy control individuals -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 4 , family members = 6/previously described in association with FH/Software predictions: Benign -
Uncertain significance, flagged submission	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, flagged submission	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham	Jan 01, 2023	The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16.This variant has been found in several FH patients including evidence of cosegregation with disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 08, 2021	This variant has been reported in multiple index patients with hypercholesterolemia in the published literature (PMID: 31491741 (2019), 23375686 (2013), 22698793 (2012), 20538126 (2010), 20145306 (2010), 18718593 (2009)). One family study indicated the variant strongly segregated with disease (PMID: 7649549 (1995)). In addition, this variant is located at an exon-intron junction and an RT-PCR study suggests the variant may affect LDLR mRNA splicing (PMID: 9763532 (1998)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published function studies demonstrate decreased residual receptor activity in cultured fibroblasts of FH heterozygotes (Guardamagna et al., 2009); Functional splice studies of a different variant at this same nucleotide position (c.2389 G>T, p.V797L) demonstrate skipping of exon 16, further supporting the functional importance of this nucleotide position (Bourbon et al., 2009); Also known as p.(V776M); This variant is associated with the following publications: (PMID: 16314194, 32759540, 30526649, 34037665, 9763532, 7649549, 11810272, 12436241, 28104544, 29233637, 27816806, 23375686, 21310417, 19318025, 20145306, 20538126, 15199436, 22859806, 22698793, 15701167, 18718593, 29874871, 27821657, 31491741, 31447099, 35339733, 34297352, 36229885, 32977124, 32331935, 33740630, 34497632, 35910211, 35913489, 35480308, 28169869, 19446849, 30710474, 33994402, 36991406, 37482509) -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2017	Variant summary: The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16. 2/4 in silico tools predict benign outcome for this variant but 5/5 splice prediction tools predict a significant impact on normal splicing. A reverse transcriptionPCR study indicated that it is likely to cause a donor site splicing error (Mak_1998). This variant was found in 1/121374 control chromosomes (including ExAC) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in several FH patients including evidence of cosegregation with disease. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 13, 2018	Pathogenic variant based on current evidence: This variant (also known as p.Val776Met in the mature protein) changes the last nucleotide in exon 16 of the LDLR mRNA (c.2389G>A). This conserved G at the last nucleotide position of an exon is known to play an important role in splicing. Although detailed splice analysis has not been performed for this variant, one study has indicated that this variant causes splicing defect and leads to absent of transcript (PMID: 9763532). A different variant at the same position (c.2389G>T) has been shown to cause an in-frame skipping of exon 16 that encodes the transmembrane domain of the LDLR protein. This demonstrates the importance of the c.2389G nucleotide in the correct splicing at the exon 16-intron 16 splice region. While this variant is rare in the general population (2/246210 chromosomes in the Genome Aggregation Database, gnomAD), it has been reported in 10+ unrelated individuals affected with familial hypercholesterolemia (PMID: 18718593, 19446849, 20145306, 22698793, 23375686). In addition, this variant has been shown to segregate with disease in 10 members from a Cuban family with familial hypercholesterolemia (PMID: 7649549). Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 797 of the LDLR protein (p.Val797Met). This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750518671, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7649549, 9763532, 19446849, 20145306, 22698793, 22859806, 23375686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226393). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2019

The p.Val797Met variant in LDLR has been reported in the heterozygous, homozygous, or compound heterozygous state in >10 individuals with familial hypercholesterolemia (FH), segregating with disease in at least 15 affected relatives from 4 families (Pereira, 1995, Mak 1998, Tichy 2012, Bertolini 2013, Setia 2016, Leren 2004). This variant has also been reported in Clinvar (Variation ID 226393). This variant has been identified in 1/30782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750518671). This variant is located in the last base of the exon, which is part of the 5’ splice region and has been shown to cause altered splicing leading to absent protein (Mak 1998). Heterozygous loss of function of the LDLR gene is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, segregation studies, low frequency in the general population and the demonstrated impact to the protein. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2021

The c.2389G>A pathogenic mutation (also known as p.V797M), located in coding exon 16 of the LDLR gene, results from a G to A substitution at nucleotide position 2389. The amino acid change results in valine to methionine at codon 797, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This alteration (also referred to as p.V776M) has been reported in a number of individuals of different origins with familial hypercholesterolemia (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22; Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Durst R et al. Atherosclerosis, 2017 Feb;257:55-63). In addition, this alteration segregated with the disease in a multi-generation family (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22). One study suggested that this alteration would affect the splicing as only the wild type allele was detected by the reverse transcription (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Benign

0.97

Eigen

Benign

0.010

Eigen_PC

Benign

0.033

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.31

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.38

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PROVEAN

Benign

0.24

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.014

Vest4

0.15

MVP

1.0

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

0.93

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

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