chr19-11129596-A-G

Variant names:

• chr19-11129596-A-G
• rs879255215
• NM_000527.5:c.2473A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5 PM2 PP3 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PM5) 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: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.93.PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnostic criteria. One index case fulfil criteria of TC > 8mmol/l and strong family history of CAD, Laurie et al, 2004, Canterbury Health Laboratories, New Zealand, PMID:15556094. One index case with DLCN score ≥6, Meshkov et al, 2021, National Medical Research Center for Therapy and Preventive Medicine, Russia, PMID:33418990.PM5: Two other missense variants in the same codon: NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines, therefore PM5 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585869/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 9.11
• Publications: 2 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PM5: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2473A>G	p.Asn825Asp	missense	Exon 17 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2473A>G	p.Asn825Asp	missense	Exon 17 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2350A>G	p.Asn784Asp	missense	Exon 16 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.2473A>G	p.Asn825Asp	missense	Exon 17 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2731A>G	p.Asn911Asp	missense	Exon 17 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2473A>G	p.Asn825Asp	missense	Exon 17 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Hypercholesterolemia, familial, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.92		Gain of phosphorylation at Y828 (P = 0.0962)
MVP		1.0
MPC		0.86
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs879255215; hg19: chr19-11240272;