19-11089549-A-G

Position:

• chr19-11089549-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5 PVS1_Moderate PM2 PS4_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1A>G (p.Met1Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PM5, PS4_Supporting, and PP4 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:PM2 - variant is absent from gnomAD (v2.1.1).PVS1_Moderate – variant is predicted to affect the initiation codon.PS4_Supporting – variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH (3 cases with SB criteria from PMID:11462246).PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines.2) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines.3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines.4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584719/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR ENST00000558518.6 start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: 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.
• PM5: 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>G	p.Met1?	start_lost	1/18	ENST00000558518.6	NP_000518.1
LDLR-AS1	NR_163945.1	n.111T>C		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>G	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: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 22, 2022	The NM_000527.5(LDLR):c.1A>G (p.Met1Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PM5, PS4_Supporting, and PP4 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: PM2 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PS4_Supporting – variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH (3 cases with SB criteria from PMID: 11462246). PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. 4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2021

The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the LDLR gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant (also referred to as M-21V) has been detected in several individuals reported to have familial hypercholesterolemia (FH), and was reported to segregation hypercholesterolemia in a family (Lombardi P et al. Clin Genet. 1997 Jun;51(6):430-1; Nauck MS et al. Hum Mutat. 2001 Aug;18(2):165-6; van der Graaf A et al. Circulation. 2011 Mar;123(11):1167-73). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

This sequence change affects the initiator methionine of the LDLR mRNA. The next in-frame methionine is located at codon 264. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with familial hypercholesterolemia (PMID: 9237510, 21382890). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 250967). 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.
Eigen	Benign	0.022
Eigen_PC	Benign	-0.082
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	0.89	D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.32	B;.;.;.;.;.
Vest4		0.68
MutPred		0.56		Loss of disorder (P = 0.1071);Loss of disorder (P = 0.1071);Loss of disorder (P = 0.1071);Loss of disorder (P = 0.1071);Loss of disorder (P = 0.1071);Loss of disorder (P = 0.1071);
MVP		0.99
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.88

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;