rs879254830

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_000527.5(LDLR):​c.1207_1209delTTC​(p.Phe403del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: not found (cov: 29)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:1

Conservation

PhyloP100: 7.92
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a strand (size 4) in uniprot entity LDLR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000527.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 19-11113292-CTCT-C is Pathogenic according to our data. Variant chr19-11113292-CTCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251731.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.1207_1209delTTC p.Phe403del conservative_inframe_deletion Exon 9 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.1207_1209delTTC p.Phe403del conservative_inframe_deletion Exon 9 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1460964
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
726802
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5Uncertain:1
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PM4+PS4_Moderate+PP4 -

Nov 05, 2016
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 16, 2016
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 -

Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

May 24, 2021
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 27, 2023
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.1207_1209del (p.Phe403del) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM4, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (v2.1.1). PM4: Variant meets PM2 and is an in-frame deletion. PS4_Supporting, PP4: Variant meets PM2 and was identified in at least 5 unrelated index cases who fulfill criteria for FH (4 patients from PMID 22698793 (Tichý et al., 2012) and 1 patient from PMID 11462246 (Nauck et al., 2001), reported as 1205delTCT). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs879254830; hg19: chr19-11223968; API