19-11116969-G-T

Position:

chr19-11116969-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - 2 informative meioses identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023592/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:17B:1O:1

Conservation

PhyloP100: 1.67

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 Uncertain_significance. Variant got 1 ACMG points.

PP1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1816G>T	p.Ala606Ser	missense_variant	12/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1816G>T	p.Ala606Ser	missense_variant	12/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251476

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135908

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000278

AC:

407

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

188

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000360

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000151

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000963

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:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000882

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:11Benign:1

Uncertain significance, 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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Aug 07, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 11, 2022	- -
Uncertain significance, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jun 17, 2019	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 09, 2021	The NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - 2 informative meioses identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 23, 2022	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/220 non-FH alleles -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant (also known as p.Ala585Ser in the mature protein) replaces alanine with serine at codon 606 of the LDLR 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). Functional studies have shown that this variant has neutral LDLR expression, LDLR binding and LDL uptake activity compared to wild type, suggesting this variant may not disrupt LDLR function (PMID: 25647241, 32015373). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9409298, 9544745, 14974088, 15199436, 16250003, 17765246, 18325082, 25647241, 27765764). It has also been reported in an individual affected with hypoalphalipoproteinemia (PMID: 35460704). This variant has also been identified in 31/282830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial hypercholesterolemia

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	This sequence change replaces alanine with serine at codon 606 of the LDLR protein (p.Ala606Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs72658865, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 9409298, 9544745, 14974088, 15199436, 16250003, 17765246, 18325082, 24956927, 27765764). This variant is also known as p.Arg585Ser. ClinVar contains an entry for this variant (Variation ID: 161264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 32015373). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 26, 2023	This missense variant (also known as p.Ala585Ser in the mature protein) replaces alanine with serine at codon 606 of the LDLR 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). Functional studies have shown that this variant has neutral LDLR expression, LDLR binding and LDL uptake activity compared to wild type, suggesting this variant may not disrupt LDLR function (PMID: 25647241, 32015373). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9409298, 9544745, 14974088, 15199436, 16250003, 17765246, 18325082, 25647241, 27765764). It has also been reported in an individual affected with hypoalphalipoproteinemia (PMID: 35460704). This variant has also been identified in 31/282830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2023	Variant summary: LDLR c.1816G>T (p.Ala606Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251476 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (8e-05 vs 0.0013), allowing no conclusion about variant significance. c.1816G>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Sun_1997, Leren_2004, Dedoussis_2004, Alves_2021, Dong_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (e.g. Thormaehlen_2015, Alves_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34167030, 14974088, 35460704, 15199436, 9409298, 25647241). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Hypercholesterolemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2021

The p.A606S variant (also known as c.1816G>T), located in coding exon 12 of the LDLR gene, results from a G to T substitution at nucleotide position 1816. The alanine at codon 606 is replaced by serine, an amino acid with similar properties. This variant has been reported in numerous familial hypercholesterolemia (FH) cohorts; however, limited clinical information was provided (Sun XM et al. Arterioscler Thromb Vasc Biol, 1997 Nov;17:3092-101; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Taylor A et al. Clin Genet, 2007 Jun;71:561-8; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Leigh SE et al. Ann Hum Genet, 2008 Jul;72:485-98; Norsworthy PJ et al. BMC Med. Genet., 2014 Jun;15:70; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Medeiros AM et al. Genet Med, 2016 Apr;18:316-24; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445). Additionally, an in vitro study showed this alteration may not impact protein function (Galicia-Garcia U et al. Sci Rep, 2020 02;10:1727). This amino acid position is well 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

not provided, no classification provided

in vitro

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.;.;.;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.55

D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

0.57

N;.;.;.;.;N

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N;N;N;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.43

T;T;T;T;T;T

Sift4G

Benign

0.61

T;T;T;T;T;T

Polyphen

0.067

B;.;.;.;.;.

Vest4

0.14

MVP

1.0

MPC

0.47

ClinPred

0.19

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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