19-11105537-C-T

Position:

chr19-11105537-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000527.5(LDLR):c.631C>T(p.His211Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H211L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 7.78

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 11 ACMG points.

PM1

In a strand (size 3) in uniprot entity LDLR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11105538-A-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 19-11105537-C-T is Pathogenic according to our data. Variant chr19-11105537-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251335.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Uncertain_significance=1, Pathogenic=4}. Variant chr19-11105537-C-T is described in Lovd as [Pathogenic]. Variant chr19-11105537-C-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.631C>T	p.His211Tyr	missense_variant	4/18	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.631C>T	p.His211Tyr	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250972

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00000274

AC:

AN:

1461450

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 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	Jan 08, 2024	This missense variant replaces histidine with tyrosine at codon 211 of the LDLR protein. This variant is also known as p.His190Tyr in the mature protein. This variant alters a conserved histidine residue in the ligand binding domain LDLR type A repeat 4 of the LDLR protein LDLR type A repeat 4 (a.a. 146-186), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that this variant has a mild impact on LDLR protein expression and function (PMID: 15494314, 15741231, 19674976, 21511053). This variant has been reported in four siblings affected with familial hypercholesterolemia (PMID: 10570905) and in three unrelated individuals affected with familial hypercholesterolemia (UMD, PMID: 23064986; communication with external laboratories: ClinVar SCV002660614.1, UMD). It has also been reported in 6 individuals suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has been identified in 3/250972 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 18, 2022	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 17, 2018	Variant p.His211Tyr in LDLR c.631C>T in exon 4 (NM_000527.4, hg19, chr19-11216213-C-T) This variant is also known as p.His190Tyr in the literature. SCICD classification Pathogenic We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: moderate case and segregation data, strong functional studies and rarity in the general population. Gene-level evidence LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data summary Cases (not including our patient): At least 3 individuals with FH or homozygous FH. Segregated with disease in 4 additional family members from one of these families. Found in two family members who did not have elevated cholesterol, one of whom was 3 years old at the time of testing. ClinVar: classified as likely pathogenic by one lab and pathogenic by onelabs. The Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum has also seen this variant but do not provide a classification. Please see below for a detailed review of case data. Predicted Consequence Per the test report, "This sequence change replaces histidine with tyrosine at codon 211 of the LDLR protein (p.His211Tyr)." Histidine is a positively charged amino acid whereas tyrosine is an amino acid with a hydrophobic side chain. Experimental Data Detailed functional studies have shown that this missense change impairs LDLR protein function in vitro. This is true for this variant as well as for others at this codon. This variant is located in a region of the LDL receptor (LA4) that is important for binding LDL molecules. Conservation Per the test report, "The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine." The amino acid histidine is strongly, though not completely conserved in aligned species in the UCSC genome browser. Nearby pathogenic variation Per Varsome.org, there is another variant present in ClinVar at this codon, with conflicting interpretations. There are several other nearby pathogenic or likely pathogenic variants listed in ClinVar per Varsome.org Population Data Highest MAF in Latino population: 0.0059%. Metrics indicate adequate coverage. Please see below for details. Case data for p.His211Tyr in LDLR (does not include this patient): At least 6 individuals with familial hypercholesterolemia have this variant. This variant was reported to segregate in 4 individuals in one family with FH. The variant was present in two individuals who did not have high cholesterol, though one was only 3 years old. The authors attributed this to age-dependent penetrance. We consider this moderate segregation data. ClinVar: Pathogenic: Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge Likely pathogenic: LDLR-LOVD, British Heart Foundation No interpretation: Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum Cases in the literature: At least 3 individuals with FH or homozygous FH. This variant segregated with disease in 4 family members tested. An additional family member did not have the phenotype but had the variant. A young child did not have elevated cholesterol but was only 3 years of age. Hopkins et al 1999: Variant referred to as p.His190Tyr in this paper. Caucasian proband from Utah with LDL cholesterol levels of 277 mg/dL and their affected relatives with high cholesterol (see pedigree below) underwent sequencing of the LDLR gene which revealed p.His190Tyr. This variant segregated in all family members with elevated cholesterol (shaded in black in the diagram below). It is important to note ages here. The reduced -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 21, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2024	Functional studies demonstrate this variant decreases the lipoprotein-binding capacity of the LDL receptor through reduction in the number of surface receptors; however, the effect on surface expression did not reach statistical significance (PMID: 21511053); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as H190Y; This variant is associated with the following publications: (PMID: 15494314, 15741231, 18847225, 29204877, 26755827, 10570905, 32719484, 34037665, 23064986, 34906454, 21511053, 38852422, 30583242) -

Familial hypercholesterolemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 03, 2020	The c.631C>T (p.His211Tyr) variant in the LDLR gene is located on the exon 4 and is predicted to replace histidine with tyrosine at codon 211 (p.His211Tyr). The variant has been identified in an individual with familial hypercholesterolemia (FH) (PMID: 23064986). It segregated with FH phenotype in 4 informative meiosis in a family (LDL-c higher than 190 mg/dL) (PMID: 10570905). Functional study of this variant with LDLR deficient fibroblast cells showed the LDL uptake was close to 70% of WT and had marginal impact (PMID: 21511053). The variant has been reported in ClinVar (ID: 251335). The variant is rare in the general population according to gnomAD (3/250972, PopMax MAF<0.02%). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.896). Therefore, the c.631C>T (p.His211Tyr) variant of LDLR has been classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2023	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. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 211 of the LDLR protein (p.His211Tyr). This variant is present in population databases (rs771917370, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1057090, 23064986). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His190Tyr. ClinVar contains an entry for this variant (Variation ID: 251335). Experimental studies have shown that this missense change affects LDLR function (PMID: 21511053). This variant disrupts the p.His221 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17347910, 27784735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2023	This missense variant replaces histidine with tyrosine at codon 211 of the LDLR protein. This variant is also known as p.His190Tyr in the mature protein. This variant alters a conserved histidine residue in the ligand binding domain LDLR type A repeat 4 of the LDLR protein LDLR type A repeat 4 (a.a. 146-186), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that this variant has a mild impact on LDLR protein expression and function (PMID: 15494314, 15741231, 19674976, 21511053). This variant has been reported in four siblings affected with familial hypercholesterolemia (PMID: 10570905) and in three unrelated individuals affected with familial hypercholesterolemia (UMD, PMID: 23064986; communication with external laboratories: ClinVar SCV002660614.1, UMD). It has also been reported in 6 individuals suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has been identified in 3/250972 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is 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 16, 2019

The p.His211Tyr variant in LDLR (also described as p.His190Tyr in the literature) has been reported in the heterozygous state in 2 individuals with familial hypercholesterolemia (FH) and segregated with disease in 4 affected relatives from 1 family (Hopkins 1999, Ahmad 2012). It has also been reported by other clinical laboratories in ClinVar (Variation ID 251335) and has been identified in 3/250972 of pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. An in vitro functional study and computational prediction tools support an impact to the protein. 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 FH. ACMG/AMP criteria applied: PM2, PP1, PP3, PS3_Supporting, PS4_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2021

The p.H211Y pathogenic mutation (also known as c.631C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 631. The histidine at codon 211 is replaced by tyrosine, an amino acid with similar properties, and is located in the ligand binding domain. This alteration, historically described as p.H190Y, has been detected in individuals with familial hypercholesterolemia (FH), with segregation reported in at least four affected relatives from one family (Hopkins PN et al. J. Hum. Genet., 1999;44:364-7; Ahmad Z et al. Circ Cardiovasc Genet, 2012 Dec;5:666-75). Internal structural analysis has determined this variant to be located in an LDLR hotspot region, and alternate amino acid substitutions at this position, p.H211L (p.H190L) and p.H211D (p.H190D), have been reported in FH cohorts (Rudenko G et al. Science, 2002 Dec;298:2353-8; Widhalm K et al. J. Inherit. Metab. Dis., 2007 Apr;30:239-47; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 18, 2018

Variant summary: LDLR c.631C>T (p.His211Tyr) results in a conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of 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 1.2e-05 in 246024 control chromosomes (gnomAD). The variant, c.631C>T, has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Ahmad_2012), but was also found to not segregate with disease in one family study (Hopkins_1999). Since the penetrance of Familial Hypercholesterolemia (0.75) due to this variant appears to be lower than expected (0.8) and no individual in the family study had a history of coronary artery disease or tendon xanthomas, no conclusions can be drawn from these data. Two different missense substitutions at the same codon as the variant of interest (c.631C>G (His 211Asp) and c.632A>T (H190L)) have been reported in individuals affected with familial hypercholesterolemia (Sanchez-Hernandez_2016, Widhalm_2007), suggesting this codon might be functionally important. In vitro studies have shown that mutation of any individual LDLR histidine to tyrosine (H190Y, H562Y, or H586Y; legacy names) does not interfere with the ability of the receptor to bind LDL at neutral pH on the cell surface, nor is the LDL-release activity diminished by more than about 30% when compared with normal LDLR activity, with one of the authors suggesting that this variant might be a receptor polymorphism (Huang_2010, Beglova_2004). However, it has been shown that when all three histidines are simultaneously replaced by either alanine or tyrosine, the mutant receptor loses the ability to release bound LDL (Huang_2010). These studies suggest that in isolation, this variant has little functional impact on LDL binding or release. One ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic, while two literature reviews cite it as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic, until more definitive functional and clinical data become available. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

L;.;.;L

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Benign

0.070

T;T;T;T

Sift4G

Uncertain

0.036

D;T;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.69

MutPred

0.76

Loss of disorder (P = 0.0428);Loss of disorder (P = 0.0428);.;Loss of disorder (P = 0.0428);

MVP

1.0

MPC

0.87

ClinPred

0.95

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.70

gMVP

0.92

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