19-11120471-G-C

Variant names:

• chr19-11120471-G-C
• rs776217028
• NM_000527.5:c.2089G>C

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.2089G>C (p.Ala697Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL=0.78.PS4_Supporting, PP4: Variant meets PM2, and is identified in at least 5 unrelated index cases who fulfil FH criteria. One index case who fulfils Simon Broome definite FH criteria reported in PMID 23669246 (supplementary Table 2) by Futema et al, 2013 from University College London, UK. One index case who fulfils Simon Broome criteria for FH reported in PMID 17094996 (Table 2) by Tosi et al, 2007 from Imperial College London, UK. Three index cases fulfil DLCN ≥6 reported in PMID 33418990 (Appendix Table A1) by Meshkov et al, 2021 from National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia.PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family, 2 affected relatives with definite FH by Simon Broome criteria and tested positive for the variant, reported in PMID 23669246 (supplementary Table 2) by Futema et al, 2013 from University College London, UK. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585767/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
• Conservation: PhyloP100: 4.28

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.2089G>C	p.Ala697Pro	missense_variant	Exon 14 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2089G>C	p.Ala697Pro	missense_variant	Exon 14 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Oct 28, 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.2089G>C (p.Ala697Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL=0.78. PS4_Supporting, PP4: Variant meets PM2, and is identified in at least 5 unrelated index cases who fulfil FH criteria. One index case who fulfils Simon Broome definite FH criteria reported in PMID 23669246 (supplementary Table 2) by Futema et al, 2013 from University College London, UK. One index case who fulfils Simon Broome criteria for FH reported in PMID 17094996 (Table 2) by Tosi et al, 2007 from Imperial College London, UK. Three index cases fulfil DLCN ≥6 reported in PMID 33418990 (Appendix Table A1) by Meshkov et al, 2021 from National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia. PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family, 2 affected relatives with definite FH by Simon Broome criteria and tested positive for the variant, reported in PMID 23669246 (supplementary Table 2) by Futema et al, 2013 from University College London, UK. -

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
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.94	D;.;.;.;.
Eigen	Benign	0.044
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;H
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.89	P;.;.;.;.
Vest4		0.79
MutPred		0.88		Gain of disorder (P = 0.0329);Gain of disorder (P = 0.0329);.;.;Gain of disorder (P = 0.0329);
MVP		1.0
MPC		0.81
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.98
gMVP		0.96

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: rs776217028; hg19: chr19-11231147;