19-11089549-A-T

Position:

• chr19-11089549-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP4 PS4_Supporting PS3 PS1 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1A>T (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS1, PS3, PM2, PVS1_Moderate, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PS1 - One more missense variant that leads to the same amino acid change: (1)NM_000527.5(LDLR):c.1A>C (p.Met1Leu) (ClinVar ID 250966) - Pathogenic by these guidelines--- variant is classified as Pathogenic, so PS1 is Met.PS3 - Level 1 (and other levels) FS: Graça et al., 2021 (PMID 34572405) Heterologous cells (CHO), FACS, luciferase and microscopy assays: FACS: 10% cell surface LDLR, 3% binding and 8% uptake; luciferase : 1% luciferase construct activity; microscopy: 5-10% LDLR expression and 5-10% LDLR activity.--- functional study in heterologous cells results in expression, binding and uptake less than 70% of wild-type, so PS3 is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PVS1_moderate - Variant is in initiation codon, so PVS1_Moderate is Met.PS4_supporting - Variant meets PM2 and was identified in:- 1 index case with DLCN score above 6 from University of British Columbia, Canada;- 1 index case with Simon-Broome criteria of possible FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 1 index case with Simon-Broome criteria of possible FH (Inclusion: LDL-C level>95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, and a family history of hypercholesterolemia and cardiovascular disease) from PMID:21382890 (van der Graaf et al., 2011), The Netherlands;- 1 index case with Simon-Broome criteria of at least possible FH from PMID:17094996 (Tosi et al., 2007), UK.--- 4 cases, so PS4_Supporting is MetPP4 - Variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584720/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 2.21

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]

LDLR-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1A>T	p.Met1?	start_lost	1/18	ENST00000558518.6	NP_000518.1
LDLR-AS1	NR_163945.1	n.111T>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1A>T	p.Met1?	start_lost	1/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 17, 2022	The NM_000527.5(LDLR):c.1A>T (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS1, PS3, PM2, PVS1_Moderate, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS1 - One more missense variant that leads to the same amino acid change: (1)NM_000527.5(LDLR):c.1A>C (p.Met1Leu) (ClinVar ID 250966) - Pathogenic by these guidelines --- variant is classified as Pathogenic, so PS1 is Met. PS3 - Level 1 (and other levels) FS: Graça et al., 2021 (PMID 34572405) Heterologous cells (CHO), FACS, luciferase and microscopy assays: FACS: 10% cell surface LDLR, 3% binding and 8% uptake; luciferase : 1% luciferase construct activity; microscopy: 5-10% LDLR expression and 5-10% LDLR activity. --- functional study in heterologous cells results in expression, binding and uptake less than 70% of wild-type, so PS3 is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PVS1_moderate - Variant is in initiation codon, so PVS1_Moderate is Met. PS4_supporting - Variant meets PM2 and was identified in: - 1 index case with DLCN score above 6 from University of British Columbia, Canada; - 1 index case with Simon-Broome criteria of possible FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 1 index case with Simon-Broome criteria of possible FH (Inclusion: LDL-C level>95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, and a family history of hypercholesterolemia and cardiovascular disease) from PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; - 1 index case with Simon-Broome criteria of at least possible FH from PMID: 17094996 (Tosi et al., 2007), UK. --- 4 cases, so PS4_Supporting is Met PP4 - Variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is Met. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Dec 16, 2020	The heterozygous c.1A>T (p.Met1?) variant identified in the LDLR gene affects the translation-initiator Methionine and is predicted to abolish the synthesis of a normal LDLR molecule. The variant has been reported in multiple individuals affected with familial hypercholesterolemia [PMID: 8831933, 21382890, and more]. The variant is reported in ClinVar as Pathogenic/Likely Pathogenic by multiple independent laboratories [VarID:250968]. The c.1A>T (p.Met1?) variant is absent from the gnomAD database indicating it is an extremely rare allele in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools. Based on the available evidence, the c.1A>T (p.Met1?) variant identified in the LDLR gene is reported as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 03, 2022	- -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2023

Disruption of the initiator codon has been observed in individual(s) with familial hypercholesterolemia (PMID: 8831933, 21382890, 23680767). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). ClinVar contains an entry for this variant (Variation ID: 250968). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the LDLR mRNA. The next in-frame methionine is located at codon 264. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Uncertain	0.48	T;.;.;.;.;.
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	-0.69	N;N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.17	B;.;.;.;.;.
Vest4		0.70
MutPred		0.57		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.96
gMVP		0.85

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: rs879254382; hg19: chr19-11200225;