rs879254382

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-11089549-A-C
• chr19-11089549-A-G
• chr19-11089549-A-T

Variant summary

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

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 NM_000527.5 initiator_codon
• 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: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

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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 18	1	NM_000527.5	ENSP00000454071.1

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

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

0/190 non-FH alleles; 0/200 normal chromosomes -

Apr 22, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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
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;