19-11113590-G-T

Position:

chr19-11113590-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.1414G>T(p.Asp472Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 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. D472N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 1 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17B:1O:1

Conservation

PhyloP100: 2.58

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 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11113590-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 19-11113590-G-T is Pathogenic according to our data. Variant chr19-11113590-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113590-G-T 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.1414G>T	p.Asp472Tyr	missense_variant	10/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1414G>T	p.Asp472Tyr	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152132

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251206

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135804

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 SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Benign:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:7Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2024	This missense variant replaces aspartic acid with tyrosine at codon 472 of the LDLR protein. This variant is also known as p.Asp451Tyr in the mature protein. This variant alters a conserved aspartic acid residue in the LDLR type B repeat 2 of the LDLR protein (aa 439-485), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study has demonstrated that the mutant protein is partially defective in LDLR activity due to impaired protein expression or instability (PMID: 25647241). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 17196209, 17196209, 21310417, 22698793, 23375686, 27542166, 28008010, 27542166, 28008010, 35101175, 37129685; Fife 2021 https://doi.org/10.1101/2021.08.12.21261563; Alieva 2022, dissertation, University of Milan) and is reported to be associated with mild symptoms. This variant has also been shown to segregate with disease in two families (PMID: 17196209, 27542166). This variant has been identified in 15/282578 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely benign, flagged submission	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	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 03, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	LDLR NM_000527.4 exon 10 p.Asp472Tyr (c.1414G>T): This variant has been reported in the literature in the heterozygous state in several individuals with elevated LDL-C levels and/or a history of myocardial infaction, segregating with disease in multiple affected family members (Campagna 2008 PMID:17196209, Tichy 2012 PMID:22698793, Bertolini 2013 PMID:23375686, Do 2015 PMID:25487149, Thormaehlen 2015 PMID:25647241, Vohnout 2016 PMID:27542166). This variant is also present in 0.01% (5/30612) of South Asian alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/19-11224266-G-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:183116). Evolutionary conservation suggests that this variant may not impact the protein, but computational predictive tools do suggest an impact. In addition, an in vitro functional study predicts that this variant will impact the protein (Thormaehlen 2015 PMID:25647241). However, this study may not accurately represent in vivo biological function. Of note, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

not provided

Pathogenic:4Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2016	The D472Y c.1414 GAC>TAC variant in the LDLR gene has been published previously as a disease-causing variant in association with hypercholesterolemia (Campagna et al., 2008; Bertolini et al., 2013). Based on the ACMG recommendations, D472Y is interpreted as a known pathogenic sequence change. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LDLR: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2022	PP1, PM2_supporting, PM3, PS3_supporting, PS4 -

Familial hypercholesterolemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 11, 2023	This missense variant replaces aspartic acid with tyrosine at codon 472 of the LDLR protein. This variant is also known as p.Asp451Tyr in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has demonstrated that the mutant protein is partially defective in LDLR activity due to impaired protein expression or instability (PMID: 25647241). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 17196209, 17196209, 21310417, 22698793, 23375686, 27542166, 28008010, 27542166, 28008010, 35101175, 37129685; Fife 2021 https://doi.org/10.1101/2021.08.12.21261563; Alieva 2022, dissertation, University of Milan) and is reported to be associated with mild symptoms. This variant has also been shown to segregate with disease in two families (PMID: 17196209, 27542166). This variant has been identified in 15/282578 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 472 of the LDLR protein (p.Asp472Tyr). This variant is present in population databases (rs730882102, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 17196209, 21310417, 22698793, 23375686, 27542166, 27824480, 28008010, 28161202). It has also been observed to segregate with disease in related individuals. This variant is also known as p.D451Y. ClinVar contains an entry for this variant (Variation ID: 183116). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2023	Variant summary: LDLR c.1414G>T (p.Asp472Tyr) results in a non-conservative amino acid change located in the class B repeat domain (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251206 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (5.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1414G>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g., Bertolini_2013, Futema_2021, Hou_2020, Tichy_2012, Abul-Husn_2016, DiTaranto_2021) where it is also shown to segregate with the disease in at least two families (e.g., Vohnoout_2016, Campagna_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports that the variant affects LDLR protein function, suggesting that the variant disrupts either LDLR biosynthesis or turnover (e.g., Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 28008010, 23375686, 17196209, 34297352, 25487149, 21310417, 32820175, 33508743, 31980526, 30312929, 23833242, 25647241, 22698793, 27542166). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, with 11 submitters classifying the variant as likely pathogenic/pathogenic and one submitter classifying it as likely benign. Additionally, there are other missense variants reported in the Human Gene Mutation Database (HGMD) affecting the same and/or nearby codons (example: p.S470C, p.D472N, p.I473N) associated with Hypercholesterolaemia suggesting this region may be clinically significant. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2021

The p.Asp472Tyr variant in LDLR (also described as p.Asp451Tyr in the literature) has been reported in >15 individuals with familial hypercholesterolemia (FH) and 12 individuals who had a myocardial infarction, and segregated with disease in 3 affected relatives from 2 families (Abul-Husn 2016 PMID: 28008010, Vohnout 2016 PMID: 27542166, Thormaehlen 2015 PMID: 25647241, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Campagna 2008 PMID: 17196209, ClinVar submission IDs: SCV000503344.1, SCV000540817.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183116) and has been identified in 0.02% (5/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, and in vitro functional assays were unclear in their overall impact (Thormaehlen 2015 PMID: 25647241). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP1. -

LDLR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2024

The LDLR c.1414G>T variant is predicted to result in the amino acid substitution p.Asp472Tyr. This variant is also known as p.Asp451Tyr in the literature and has been reported in more than 10 individuals with familial hypercholesterolemia and myocardial infarction (Campagna et al. 2008. PubMed ID: 17196209; Tichý et al. 2012. PubMed ID: 22698793; Do et al. 2015. PubMed ID: 25487149; Vohnout et al. 2016. PubMed ID: 27542166; Hou et al. 2020. PubMed ID: 31980526). Functional studies suggested that p.Asp472Tyr substitution could impact normal protein function (Thormaehlen et al. 2015. PubMed ID: 25647241). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic and likely pathogenic by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183116/). Of note, a different variant impacting the same amino acid (p.Asp472Asn) has been reported to be associated with familial hypercholesterolemia (Marmontel et al. 2018. PubMed ID: 29572815). Based on this evidence, we interpret the c.1414G>T (p.Asp472Tyr) as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2024

The c.1414G>T (p.D472Y) alteration is located in exon 10 (coding exon 10) of the LDLR gene. This alteration results from a G to T substitution at nucleotide position 1414, causing the aspartic acid (D) at amino acid position 472 to be replaced by a tyrosine (Y). Based on data from gnomAD, the T allele has an overall frequency of 0.005% (15/282578) total alleles studied. The highest observed frequency was 0.016% (5/30612) of South Asian alleles. This variant has been reported in individuals with familial hypercholesterolemia and was reported to segregate with disease in two small families (Campagna, 2008; Tichý, 2012; Bertolini, 2013; Vohnout, 2016; Gabová, 2017; Ibarretxe, 2018). This amino acid position is well conserved in available vertebrate species. A high-throughput in vitro assay suggested that this variant results in deficient protein function (Thormaehlen, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;.;.;.;.;.

Eigen

Benign

0.084

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.3

M;.;.;.;.;M

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.0

D;D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.010

D;D;D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D

Polyphen

0.78

P;.;.;.;.;.

Vest4

0.62

MutPred

0.88

Gain of catalytic residue at P476 (P = 0.0707);Gain of catalytic residue at P476 (P = 0.0707);.;.;.;Gain of catalytic residue at P476 (P = 0.0707);

MVP

1.0

MPC

0.82

ClinPred

0.62

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

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