19-11102724-C-T

Variant names:

• chr19-11102724-C-T
• rs875989892
• NM_000527.5:c.251C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP1_Moderate PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.251C>T (p.Pro84Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PP1_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1)PP1_Moderate - Variant segregates with FH phenotype in at least 4 informative meiosis from 2 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). In one family 2 family members positive for variant with LDL > 75th percentile, in the other 2 family members negative for variantwith LDL < 50th percentile.PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576272/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:3
• Conservation: PhyloP100: 4.87

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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	c.251C>T	p.Pro84Leu	missense_variant	Exon 3 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.251C>T	p.Pro84Leu	missense_variant	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:2

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 26, 2023

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.Pro63Leu in the mature protein) replaces proline with leucine at codon 84 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 22883975, 33740630). This variant has not been identified 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. -

Oct 07, 2011

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 20, 2023

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.251C>T (p.Pro84Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PP1_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1) PP1_Moderate - Variant segregates with FH phenotype in at least 4 informative meiosis from 2 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). In one family 2 family members positive for variant with LDL > 75th percentile, in the other 2 family members negative for variantwith LDL < 50th percentile. PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) after alternative causes of high cholesterol were excluded. -

Familial hypercholesterolemia Pathogenic:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the LDLR protein (p.Pro84Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypercholesterolemia (PMID: 22883975, 33740630). ClinVar contains an entry for this variant (Variation ID: 226310). 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.Pro84 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16159606, 33740630). 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. -

Cardiovascular phenotype Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P84L variant (also known as c.251C>T), located in coding exon 3 of the LDLR gene, results from a C to T substitution at nucleotide position 251. The proline at codon 84 is replaced by leucine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with familial hypercholesterolemia (FH) (Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;M;M;M
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-7.6	D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;T;T;D
Sift4G	Pathogenic	0.0010	D;D;T;T;D
Polyphen		0.97	D;.;.;.;.
Vest4		0.62
MutPred		0.68		Gain of MoRF binding (P = 0.0393);Gain of MoRF binding (P = 0.0393);Gain of MoRF binding (P = 0.0393);Gain of MoRF binding (P = 0.0393);Gain of MoRF binding (P = 0.0393);
MVP		0.99
MPC		0.80
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.80
gMVP		0.99

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: rs875989892; hg19: chr19-11213400;