rs879254851

Variant names:

• chr19-11113368-T-C
• rs879254851
• NM_000527.5:c.1277T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11113368-T-C
• chr19-11113368-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PP1_Moderate PM2 PM3 PP3 PP4 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4_Moderate, PM2, PM3, PP1_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0). So, PM2 is met. PP3: REVEL=0.883. It is above 0.75, so PP3 is met. PS4_Moderate, PP4: Variant meets PM2 and is identified in 9 unrelated index cases (2 cases with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 5 cases with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille, France, published on ClinVar; 1 case with possible/definite FH by Simon-Broome criteria in PMID 33269076 (Miroshnikova et al., 2021); 1 case with DLCN score 9 in PMID 9763532 (Mak et al., 1998)). PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France: 4 affected family members have the variant.PM3: A homozygous proband is reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies with LDL of 860 mg/dL. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585383/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 6.18

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

Verdict is Likely_pathogenic. Variant got 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1277T>C	p.Leu426Pro	missense_variant	Exon 9 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1277T>C	p.Leu426Pro	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4_Moderate, PM2, PM3, PP1_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0). So, PM2 is met. PP3: REVEL=0.883. It is above 0.75, so PP3 is met. PS4_Moderate, PP4: Variant meets PM2 and is identified in 9 unrelated index cases (2 cases with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 5 cases with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille, France, published on ClinVar; 1 case with possible/definite FH by Simon-Broome criteria in PMID 33269076 (Miroshnikova et al., 2021); 1 case with DLCN score 9 in PMID 9763532 (Mak et al., 1998)). PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France: 4 affected family members have the variant. PM3: A homozygous proband is reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies with LDL of 860 mg/dL. -

Familial hypercholesterolemia Pathogenic:2

May 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 426 of the LDLR protein (p.Leu426Pro). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9763532, 25775905, 33269076; Invitae). 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.Leu426 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 28353356), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 251763). This variant is also known as L405P. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Re-evaluation of ACMG classification, scoring: PM2, PM3, PP1_supporting, PS4_supporting and PP3. PM3 and PP1_supporting criteria were supported by a submission to ClinGen Variant interface by Ana Medeiros. -

Cardiovascular phenotype Pathogenic:1

Nov 08, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L426P pathogenic mutation (also known as c.1277T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1277. The leucine at codon 426 is replaced by proline, an amino acid with similar properties. This mutation (described as legacy p.L405P) has been reported in an individual with familial hypercholesterolemia (FH) (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on internal structural assessment, this alteration disrupts the beta-propeller domain of LDLR (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). An alternate amino acid substitution at this position, p.L426R, was also reported in an FH cohort, suggesting this position is a hotspot (Rubba P et al. Eur J Prev Cardiol, 2017 07;24:1051-1059). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.4	D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.15	B;.;.;.;.;.
Vest4		0.91
MutPred		0.89		Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);.;.;.;Loss of stability (P = 0.0038);
MVP		1.0
MPC		0.69
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		1.0

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: rs879254851; hg19: chr19-11224044;