NM_000527.5:c.1856T>G

Variant names:

• chr19-11120102-T-G
• rs879255054
• NM_000527.5:c.1856T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PS4_Supporting PP3 PP4 PP1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.1856T>G (p.Phe619Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PP1) 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 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP3 Met: REVEL = 0.856, which is above the threshold of 0.75.PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Supporting Met: Variant meets PM2, and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH diagnosis from different labs. One index case is from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1), another index case is reported from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (PMID16250003, SCV000295717.2).PP1 Met: Variant segregates with FH phenotype in 2 informative meiosis in one family reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1).There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>C (p.Phe619Ser), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585656/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 1.62

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• 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.
• PP3: 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.1856T>G	p.Phe619Cys	missense_variant	Exon 13 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1856T>G	p.Phe619Cys	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Feb 10, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5 (LDLR): c.1856T>G (p.Phe619Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PP1) 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 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP3 Met: REVEL = 0.856, which is above the threshold of 0.75. PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2, and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH diagnosis from different labs. One index case is from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1), another index case is reported from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (PMID16250003, SCV000295717.2). PP1 Met: Variant segregates with FH phenotype in 2 informative meiosis in one family reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1). There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>C (p.Phe619Ser), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.83
MutPred		0.97		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;.;.;Gain of sheet (P = 0.0477);
MVP		1.0
MPC		0.97
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		1.0

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: rs879255054; hg19: chr19-11230778;