19-11100340-C-T

Position:

chr19-11100340-C-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.185C>T (p.Thr62Met) variant is classified as Uncertain significance - insufficient evidence 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 - variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023598/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:12B:2O:1

Conservation

PhyloP100: 1.42

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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.185C>T	p.Thr62Met	missense_variant	2/18	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.185C>T	p.Thr62Met	missense_variant	2/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000120

AC:

AN:

250804

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000712

AC:

104

AN:

1461216

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

726888

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000666

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000906

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:12Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:7Benign:1

Likely benign, 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	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging -
Uncertain significance, criteria provided, single submitter	literature only;research	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 23, 2021	The NM_000527.5(LDLR):c.185C>T (p.Thr62Met) variant is classified as Uncertain significance - insufficient evidence 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 - variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). -
Uncertain significance, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	May 08, 2015	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2022	- -

Familial hypercholesterolemia

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 11, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 62 of the LDLR protein (p.Thr62Met). This variant is present in population databases (rs376207800, gnomAD 0.02%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 16250003, 19446849, 19717150, 25606447, 26892515, 33303402). This variant is also known as p.Thr41Met. ClinVar contains an entry for this variant (Variation ID: 161273). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

not provided

Uncertain:1Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2023	The p.Thr62Met (also reported as p.Thr41Met) variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia, 1 individual with suspected hypercholesterolemia, 1 individual with hypertriglyceridemia, 1 individual with unspecified dyslipidemia, and 5 individuals with early myocardial infarction (MI) (Fouchier 2005 PMID: 16250003, Alonso 2009 PMID: 19318025, Guardamagna 2009 PMID: 19446849, Bertolini 2013 PMID: 23375686, Cymbron 2014 PMID: 25606447, Do 2015 PMID: 25487149, Thormaehlen 2015 PMID: 25647241, Sharifi 2016 PMID: 26892515, Sanchez-Hernandez 2019 PMID: 31153816, Dron 2020 PMID: 32041611, Gill 2021 PMID: 33303402). However, it was also observed in 4 MI-free controls in the same study (Do 2015 PMID: 25487149) and in one healthy control in another study of early-onset myocardial infarction (Khera 2019 PMID: 30586733). It has also been identified in 0.02% (3/15258) of Latine/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 161273). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant does not impact protein function (Thormaehlen 2015 PMID: 25647241, Benito-Vicente 2018 PMID: 30413722); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of the p.Thr62Met variant is uncertain. ACMG/AMP Criteria applied: PP3, BS3_supporting. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 02, 2024

Variant summary: LDLR c.185C>T (p.Thr62Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250804 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00012 vs 0.0013), allowing no conclusion about variant significance. c.185C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Fouchier_2005, Guardamagna_2009, Junyent_2010, Cymbron_2014, Sharifi_2016, Gill_2020). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Functional studies report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015, Benito-Vicente_2018, Graca_2020). The following publications have been ascertained in the context of this evaluation (PMID: 30413722, 25606447, 16250003, 33303402, 35568682, 19446849, 19717150, 34456049, 26892515, 25647241). ClinVar contains an entry for this variant (Variation ID: 161273). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypercholesterolemia

Uncertain:1

Uncertain significance, 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 06, 2022

The p.T62M variant (also known as c.185C>T), located in coding exon 2 of the LDLR gene, results from a C to T substitution at nucleotide position 185. The threonine at codon 62 is replaced by methionine, an amino acid with similar properties. This variant has been reported in hypercholesterolemia cohorts but limited clinical information was provided (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Leigh SE et al. Ann. Hum. Genet., 2008 Jul;72:485-98; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). This variant has also been detected in exome cohorts and healthy controls with limited cardiovascular history (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Do R et al. Nature, 2015 Feb;518:102-6; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). Limited functional studies have suggested no significant impact on LDLR expression, binding, or uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Benito-Vicente A et al. Sci Rep, 2018 Nov;8:16614). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

0.12

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.;.;.

Eigen

Benign

-0.0049

Eigen_PC

Benign

-0.029

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.75

T;T;T;T;T;T

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.41

T;T;T;T;T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

-0.33

N;.;N;N;N;N

MutationTaster

Benign

1.0

D;D;D;D;D;N;N

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.2

D;D;N;D;D;D

REVEL

Pathogenic

0.65

Sift

Benign

0.038

D;T;T;D;T;D

Sift4G

Uncertain

0.046

D;D;T;D;T;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.63

MVP

1.0

MPC

0.55

ClinPred

0.16

GERP RS

5.4

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.20

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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