NM_000527.5:c.1A>T

Variant names:

• chr19-11089549-A-T
• rs879254382
• NM_000527.5:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PS1 PVS1_Moderate PM2 PP4 PS4_Supporting

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 initiator_codon
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 2.21
• Publications: 118 publications found

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:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000558013.5	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 18	ENSP00000453346.1	P01130-5
	LDLR	ENST00000557933.5	TSL:5	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 18	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Hypercholesterolemia, familial, 1 (5)
1	-	-	Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.54	D
PhyloP100		2.2
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.17	B
Vest4		0.70
MutPred		0.57		Loss of loop (P = 0.1242)
MVP		1.0
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		-0.050	Neutral
Varity_R		0.96
gMVP		0.85
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879254382; hg19: chr19-11200225;