rs879255035

Variant names:

• chr19-11116976-C-A
• rs879255035
• NM_000527.5:c.1823C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11116976-C-A
• chr19-11116976-C-G
• chr19-11116976-C-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.1823C>A​(p.Pro608His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P608L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.63
• Publications: 0 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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain 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 chr19-11116976-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 252051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11116976-C-A is Pathogenic according to our data. Variant chr19-11116976-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2636939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1823C>A	p.Pro608His	missense_variant	Exon 12 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1823C>A	p.Pro608His	missense_variant	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:2

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 608 of the LDLR protein (p.Pro608His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (internal data). ClinVar contains an entry for this variant (Variation ID: 2636939). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Pro608 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9544745, 9852677, 11313767, 16250003), which suggests that this may be a clinically significant amino acid residue. 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. -

Apr 25, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1823C>A (p.Pro608His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes. c.1823C>A has been observed in individual(s) diagnosed with or with clinical features consistent with Familial Hypercholesterolemia (e.g. Haralambos_2013, Fasano_2022, Medeiros_2024, Labcorp Genetics (formerly Invitae)). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <5% of normal LDLR expression and activity (Medeiros_2024). Additionally, other variants affecting the same codon have been classified as pathogenic/likely pathogenic in ClinVar (c.1822C>T (p.Pro608Ser), c.1823C>T (p.Pro608Leu)), supporting the critical relevance of codon 608 to LDLR protein function. The following publications have been ascertained in the context of this evaluation (PMID: 35123858, 38122934). ClinVar contains an entry for this variant (Variation ID: 2636939). Based on the evidence outlined above, the variant was classified as pathogenic. -

LDLR-related disorder Pathogenic:1

Dec 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1823C>A variant is predicted to result in the amino acid substitution p.Pro608His. This variant has been reported at a scientific meeting in a family with hypercholesterolemia (https://www.atherosclerosis-journal.com/article/S0021-9150(22)01021-8/fulltext). Different missense variants that affect this same amino acid residue (p.Pro608Thr, p.Pro608Ser, p.Pro608Leu) have been reported in individuals or families with hypercholesterolemia (Chmara et al. 2010. PubMed ID: 20145306; Hirayama et al. 1998. PubMed ID: 9852677; Heath et al. 2001. PubMed ID: 11313767). This c.1823C>A (p.Pro608His) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;.;H
PhyloP100		6.6
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-8.9	D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.88
MutPred		0.93		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);
MVP		1.0
MPC		0.87
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
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: rs879255035; hg19: chr19-11227652; COSMIC: COSV52943305; COSMIC: COSV52943305;