19-11120501-G-T

Variant names:

• chr19-11120501-G-T
• rs879255142
• NM_000527.5:c.2119G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2119G>T (p.Asp707Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.973. PS3: Level 1 functional studies performed using heterologous cells (CHO) with Western blot and flow cytometry, showed <2% cell surface expression, 2% binding and 6% uptake, reported in PMID 32015373 (Galicia-Garcia et al., 2020). Activity is below 70% of wild-type, consistent with damaging effect. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN score >=6 after alternative causes of high cholesterol were excluded, reported in PMID 19318025 (Alonso et al., 2009). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585779/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 8.46
• Publications: 4 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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2119G>T	p.Asp707Tyr	missense	Exon 14 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2119G>T	p.Asp707Tyr	missense	Exon 14 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1996G>T	p.Asp666Tyr	missense	Exon 13 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2119G>T	p.Asp707Tyr	missense	Exon 14 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2377G>T	p.Asp793Tyr	missense	Exon 14 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2119G>T	p.Asp707Tyr	missense	Exon 14 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:1

Feb 23, 2024

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.2119G>T (p.Asp707Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.973. PS3: Level 1 functional studies performed using heterologous cells (CHO) with Western blot and flow cytometry, showed <2% cell surface expression, 2% binding and 6% uptake, reported in PMID 32015373 (Galicia-Garcia et al., 2020). Activity is below 70% of wild-type, consistent with damaging effect. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN score >=6 after alternative causes of high cholesterol were excluded, reported in PMID 19318025 (Alonso et al., 2009).

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		8.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.89		Loss of disorder (P = 0.0228)
MVP		1.0
MPC		0.90
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.98
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255142; hg19: chr19-11231177;