19-11113612-T-C

Variant names:

• chr19-11113612-T-C
• rs879254900
• NM_000527.5:c.1436T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PS4_Supporting PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1436T>C (p.Leu479Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: This variant is absent from gnomAD v4.0.0.PP3: REVEL= 0.949.PS4_Supporting, PP4: At least four unrelated index cases fulfil FH criteria: one reported in VCI with DLCN ≥6 from Robarts Research Institute, Canada; one case in ClinVar with probable FH by DLCNC reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France; at least one index case fulfils Simon Broome criteria, reported from UK in PMID 11313767 (Table 1), 16389549 (Table 2) and 20736250 (Table 1, Figure 1); at least one case reported in PMID 19318025 with DLCN ≥6 (Supplementary table B). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585450/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 7.92

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 Uncertain_significance. Variant got 5 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.
• 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.1436T>C	p.Leu479Pro	missense_variant	Exon 10 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1436T>C	p.Leu479Pro	missense_variant	Exon 10 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461768 Hom.: 0 Cov.: 35 AF XY: 0.00000963 AC XY: 7 AN XY: 727192

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

-

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 30, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2024

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.1436T>C (p.Leu479Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD v4.0.0. PP3: REVEL= 0.949. PS4_Supporting, PP4: At least four unrelated index cases fulfil FH criteria: one reported in VCI with DLCN =6 from Robarts Research Institute, Canada; one case in ClinVar with probable FH by DLCNC reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France; at least one index case fulfils Simon Broome criteria, reported from UK in PMID 11313767 (Table 1), 16389549 (Table 2) and 20736250 (Table 1, Figure 1); at least one case reported in PMID 19318025 with DLCN =6 (Supplementary table B). -

not provided Pathogenic:1

Jun 25, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported in association with familial hypercholesterolemia (PMID: 11313767, 37409534, 16389549, 11668627, 32041611); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L458P); This variant is associated with the following publications: (PMID: 11313767, 37589137, 37409534, 16389549, 11668627, 32719484, 32041611, 20736250) -

Cardiovascular phenotype Pathogenic:1

Nov 07, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L479P variant (also known as c.1436T>C), located in coding exon 10 of the LDLR gene, results from a T to C substitution at nucleotide position 1436. The leucine at codon 479 is replaced by proline, an amino acid with similar properties. This variant has been reported in association with familial hypercholesterolemia (FH) (Wang J et al. Hum Mutat, 2001 Oct;18:359; Heath KE et al. Eur J Hum Genet, 2001 Apr;9:244-52; Naoumova RP et al. Atherosclerosis, 2004 May;174:67-71; Taylor A et al. Ann Clin Biochem, 2010 Sep;47:487-90; Ambry internal data). This alteration was also detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 Aug;26:1235-1239). 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. 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. -

Familial hypercholesterolemia Pathogenic:1

Sep 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 251840). This variant is also known as L458P. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 11668627, 16389549, 20736250; Invitae). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 479 of the LDLR protein (p.Leu479Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;.;.;.;.;H
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;T;D;D;D;D
Polyphen		0.63	P;.;.;.;.;.
Vest4		0.92
MutPred		0.95		Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);.;.;.;Loss of stability (P = 0.0143);
MVP		1.0
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs879254900; hg19: chr19-11224288;