19-11102784-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM1PP4PP3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.311G>T (p.Cys104Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 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 (gnomAD v4.0.0).PP3: REVEL = 0.882. PM1: Variant meets PM2 and alters Cys104, one of the cysteine residues listed. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH from PMID 16159606 (Graham et al., 2005), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584839/MONDO:0007750/013

Frequency

Genomes: not found (cov: 31)

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

15
2
2
Splicing: ADA: 0.9868
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:2U:1

Conservation

PhyloP100: 9.95
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
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
LDLRNM_000527.5 linkc.311G>T p.Cys104Phe missense_variant, splice_region_variant Exon 3 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.311G>T p.Cys104Phe missense_variant, splice_region_variant Exon 3 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:1
Feb 23, 2024
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.311G>T (p.Cys104Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 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 (gnomAD v4.0.0). PP3: REVEL = 0.882. PM1: Variant meets PM2 and alters Cys104, one of the cysteine residues listed. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH from PMID 16159606 (Graham et al., 2005), after alternative causes of high cholesterol were excluded. -

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

- -

Mar 01, 2016
Iberoamerican FH Network
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;.;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D;T;D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.6
H;.;H;H;H
PrimateAI
Benign
0.41
T
PROVEAN
Pathogenic
-9.7
D;D;D;D;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.96
MutPred
0.80
Gain of catalytic residue at C104 (P = 0.0394);Gain of catalytic residue at C104 (P = 0.0394);Gain of catalytic residue at C104 (P = 0.0394);Gain of catalytic residue at C104 (P = 0.0394);Gain of catalytic residue at C104 (P = 0.0394);
MVP
1.0
MPC
1.0
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.99
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.88
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: rs875989895; hg19: chr19-11213460; COSMIC: COSV99370042; COSMIC: COSV99370042; API