19-11105326-G-T

Position:

• chr19-11105326-G-T

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000558518.6(LDLR):​c.420G>T​(p.Glu140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E140K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 26 ACMG points.

• PS1: Transcript ENST00000558518.6 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 251216
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000558518.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11105324-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 251213.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-11105326-G-T is Pathogenic according to our data. Variant chr19-11105326-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105326-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.420G>T	p.Glu140Asp	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.420G>T	p.Glu140Asp	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 07, 2023	The c.420G>T (p.Glu140Asp) variant of the LDLR gene is located on the exon 4 and is predicted to replace glutamic acid with aspartic acid at codon 140 (p.Glu140Asp). The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (PMID: 20145306, 34074024, 32491301, 23680767, 34182004, 11524740, 32770674). Alternative variant disrupting the same amino acid (p.Glu140Lys) has been interpreted as pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar ID: 251213). The p.Glu140Asp variant has been reported in ClinVar (ID: 251216). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.853). Therefore, the c.420G>T (p.Glu140Asp) variant of LDLR has been classified as pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 02, 2023	The LDLR c.420G>T (p.Glu140Asp) variant has been reported in the published literature in affected individuals with familial hypercholesterolemia (PMIDs: 21310417 (2011) and 34037665 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 21, 2016	- -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 16, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu140 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 23375686, 21722902, 11668627, 15359125, 21310417). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 21310417, 17094996, 17094996, 20145306, 11754108). This variant is also described as Glu119Asp (E119D) in the literature. ClinVar contains an entry for this variant (Variation ID: 251217). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 140 of the LDLR protein (p.Glu140Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.68
MutPred		0.98		Loss of glycosylation at S142 (P = 0.1399);Loss of glycosylation at S142 (P = 0.1399);.;Loss of glycosylation at S142 (P = 0.1399);
MVP		1.0
MPC		0.77
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879254520; hg19: chr19-11216002;