chr19-11089549-A-C

Position:

• chr19-11089549-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PS3 PP1_Moderate PM2 PS4_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1A>C (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PS3, PS4_Supporting, PP1_Moderate, 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.PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: results of 60% cell surface LDLR, 59% LDL binding and 66% LDL uptake, compared to wild-type. Note - Level 3 luciferase reporter assays were also performed: results of 5% luciferase construct activity compared to wild-type. Both studies performed in PMID:34572405.PS4_Supporting - variant meets PM2 and is identified in 4 unrelated index cases who fulfill clinical criteria for FH (4 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab).PP1_Moderate – variant segregates with phenotype in 4 informative meioses in 3 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 3 families: 4 affected relatives with the variant).PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.Note: four other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1A>G (p.Met1Val) – Likely 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. -PM5 not applicable as such variants must be Pathogenic. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584718/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR ENST00000558518.6 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• 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 12 ACMG points.

• PVS1: 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.
• PP1: 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>C	p.Met1?	start_lost	1/18	ENST00000558518.6	NP_000518.1
LDLR-AS1	NR_163945.1	n.111T>G		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>C	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:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/200 normal chromosomes -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 22, 2022	The NM_000527.5(LDLR):c.1A>C (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PS3, PS4_Supporting, PP1_Moderate, 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. PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: results of 60% cell surface LDLR, 59% LDL binding and 66% LDL uptake, compared to wild-type. Note - Level 3 luciferase reporter assays were also performed: results of 5% luciferase construct activity compared to wild-type. Both studies performed in PMID: 34572405. PS4_Supporting - variant meets PM2 and is identified in 4 unrelated index cases who fulfill clinical criteria for FH (4 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab). PP1_Moderate – variant segregates with phenotype in 4 informative meioses in 3 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 3 families: 4 affected relatives with the variant). PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Note: four other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1A>G (p.Met1Val) – Likely 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. -PM5 not applicable as such variants must be Pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

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	0.82
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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;