19-11113753-C-A

Variant names:

• chr19-11113753-C-A
• rs879254944
• NM_000527.5:c.1577C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1577C>A (p.Pro526His) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) 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).PP3 - REVEL = 0.946. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404086609/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.81
• Publications: 4 publications found

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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1577C>A	p.Pro526His	missense	Exon 10 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1577C>A	p.Pro526His	missense	Exon 10 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1454C>A	p.Pro485His	missense	Exon 9 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1577C>A	p.Pro526His	missense	Exon 10 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1835C>A	p.Pro612His	missense	Exon 10 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1577C>A	p.Pro526His	missense	Exon 10 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:2

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro526 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11462246, 25647241, 27497240; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 496019). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 24082139, 33418990; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 526 of the LDLR protein (p.Pro526His).

Jul 30, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1577C>A (p.Pro526His) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251276 control chromosomes (gnomAD). c.1577C>A has been observed in individuals affected with Familial Hypercholesterolemia (Gonzalez-Garay_2013, Meshkov_2021, internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense (c.1576C>T, p.P526S) that disrupts this residue has been determined to be pathogenic, suggesting that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. The following publications have been ascertained in the context of this evaluation (PMID: 24082139, 26283345, 33418990). ClinVar contains an entry for this variant (Variation ID: 496019). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Cardiovascular phenotype Pathogenic:1

Oct 03, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P526H variant (also known as c.1577C>A), located in coding exon 10 of the LDLR gene, results from a C to A substitution at nucleotide position 1577. The proline at codon 526 is replaced by histidine, an amino acid with similar properties. This variant was reported in individuals with features consistent with familial hypercholesterolemia (FH) (Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62; Meshkov A et al. Genes (Basel), 2021 Jan;12:[ePub ahead of print]; Ambry internal data). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Hypercholesterolemia, familial, 1 Uncertain:1

Jan 18, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_000527.5(LDLR):c.1577C>A (p.Pro526His) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) 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). PP3 - REVEL = 0.946.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.93		Loss of sheet (P = 0.0084)
MVP		1.0
MPC		0.87
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.95
gMVP		1.0
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs879254944; hg19: chr19-11224429;