rs879254603

Positions:

• chr19-11105538-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000527.5(LDLR):​c.632A>T​(p.His211Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,382 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. H211Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:2
• Conservation: PhyloP100: 4.14

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]

ACMG classification

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 chr19-11105537-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-11105538-A-T is Pathogenic according to our data. Variant chr19-11105538-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251337.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=6}. Variant chr19-11105538-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.632A>T	p.His211Leu	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	c.632A>T	p.His211Leu	missense_variant	4/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461382 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 14, 2020	The c.632A>T variant in the LDLR gene results in an amino acid change from a histidine to a leucine at codon 211 of encoded protein (p.His211Leu). Also known as p.His190Leu, this variant has been reported in a patient with familial hypercholesterolemia (PMID: 17347910). It is not present in the general population (gnomAD). Other missense variants affecting the same codon (p.His211Asp, p.His211Tyr) have been observed in unrelated individuals with familial hypercholesterolemia (PMID: 17765246, 23064986), suggesting the histidine residue is important for LDLR protein function. Multiple lines of in silico algorithms predict this p.His211Leu variant to be deleterious. Therefore, the c.632A>T (p.His211Leu) variant in the LDLR gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 30, 2024	This missense variant replaces histidine with leucine at codon 211 of the LDLR protein. This variant is also known as p.His190Leu in the mature protein. This variant alters a conserved histidine residue in the LDLR type A repeat 4 of the LDLR protein (aa 146-186), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 17347910; ClinVar SCV001539711.3) and in one individual affected with dyslipidemia (PMID: 34363016). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.His211Tyr and p.His211Asp, are considered to be disease-causing (ClinVar variation ID: 251335, 251334), suggesting that histidine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial hypercholesterolemia Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 211 of the LDLR protein (p.His211Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 17347910; Invitae). This variant is also known as p.His190Leu. ClinVar contains an entry for this variant (Variation ID: 251337). 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%. This variant disrupts the p.His211 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10570905, 21511053; Invitae). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 22, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 01, 2021	Automatically set to LPath based on study of VUS-LP variants -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2021	PP3, PM2_supporting, PM5, PS4_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2017	Variant summary: The LDLR c.632A>T (p.His211Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change in one of the low-density lipoprotein (LDL) receptor class A repeats (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to non-functioning tool). This variant is absent from the large control database ExAC (0/120210 control chromosomes). The variant has been reported in one hypercholesterolemia patient without strong evidence for pathogenicity (Widhalm_JIMD_2007). Variants affecting the same codon, p.H211Y and p.H211D (also known as p.H190Y and p.H190D, respectively) have been reported in hypercholesterolemia patients, suggesting this residue is a mutation hotspot. LDLR crystal structure study suggested functional importance of codon H211(Rudenko_2002). Taken together, due to lack of clinical and functional data, this variant is currently classified as a VUS until more evidence becomes available. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The p.H211L variant (also known as c.632A>T), located in coding exon 4 of the LDLR gene, results from an A to T substitution at nucleotide position 632. The histidine at codon 211 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in subjects with familial hypercholesterolemia (FH) (Widhalm K et al. J Inherit Metab Dis, 2007 Apr;30:239-47; Ambry internal data). Another alteration at the same codon, p.H211Y (c.631C>T), has also been described in association with FH (Hopkins PN et al. J. Hum. Genet., 1999;44:364-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.87	D;.;.;.
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	0.69	N;.;.;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.7	D;D;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.073	T;T;T;T
Sift4G	Benign	0.071	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.81
MutPred		0.94		Loss of disorder (P = 0.081);Loss of disorder (P = 0.081);.;Loss of disorder (P = 0.081);
MVP		1.0
MPC		0.88
ClinPred		0.88	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.70
gMVP		0.95

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

Other links and lift over

dbSNP: rs879254603; hg19: chr19-11216214;