19-11116969-G-T

Variant names:

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:2U:18B: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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1816G>T	p.Ala606Ser	missense_variant	Exon 12 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.1816G>T	p.Ala606Ser	missense_variant	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1		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:2Uncertain:18Benign:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:11Benign:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Aug 07, 2012

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

0/220 non-FH alleles -

Oct 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

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.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. -

Aug 22, 2019

Robarts Research Institute, Western University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 provided

Pathogenic:1Uncertain:1Other:1

Oct 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple unrelated patients tested at GeneDx and in published literature with clinical features of familial hypercholesterolemia; although, detailed clinical and segregation data were not available for many of these probands (PMID: 9409298, 14974088, 15199436, 16250003, 17765246, 24956927, 27765764, 17539906, 18325082); Published functional studies suggest no impact on protein expression or LDL-uptake (PMID: 25647241, 32015373, 34167030); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.(A585S); This variant is associated with the following publications: (PMID: 25637381, 15199436, 24956927, 9544745, 14974088, 17765246, 18325082, 25487149, 16250003, 17539906, 25647241, 9409298, 27765764, 24055113, 32015373, 34167030, 27044878, 32041611, 35460704) -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Oct 27, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1816G>T (p.Ala606Ser) variant has been reported in the published literature in several individuals and families affected with hypercholesterolemia (PMIDs: 14974088 (2004), 15199436 (2004), 17765246 (2008), 24956927 (2014), 27765764 (2016), 31345425 (2019), 36769678 (2023)). This variant occurred with other variants on the same chromosome (in cis) as part of a complex allele as well as in trans with another deleterious LDLR variant, where the phenotype appeared more severe and is suggestive of homozygous hypercholesterolemia (HoFH) (PMIDs: 26020417 (2016), 27784735 (2016)). Family studies have observed this variant to be associated with disease (PMID: 34167030 (2021)). This variant was also reported in individuals affected with cardiac disease and in controls (PMIDs: 25487149 (2015), 27050191 (2016)). However, functional studies indicate that this variant shows cell surface expression, LDL binding, and LDL uptake activities comparable to the wild-type (PMIDs: 32015373 (2020), 34167030 (2021)). The frequency of this variant in the general population, 0.00043 (22/50804 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -

Familial hypercholesterolemia

Uncertain:3

Mar 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with serine at codon 606 of the LDLR protein. This variant is also known as p.Ala585Ser in the mature protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that this variant has neutral impact on 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 more than 10 individuals affected with familial hypercholesterolemia (PMID: 9409298, 9544745, 14974088, 15199436, 16250003, 17765246, 18325082, 25647241, 27765764, 36769678). 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). A different variant affecting the same codon, p.Ala606Thr, is considered to be disease-causing (ClinVar variation ID: 252046), suggesting that alanine at this position is important for LDLR protein function. 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. -

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:2

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hypercholesterolemia

Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype

Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

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