rs773693079

Variant names:

• chr19-11120221-A-C
• rs773693079
• NM_000527.5:c.1975A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PS4_Supporting PP4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1975A>C (p.Thr659Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 15 May 2023. The supporting evidence is as follows:PM2: PopMax MAF = 0.0001853 (0.01853%) in European (Finnish) exomes (gnomAD v2.1.1).PS4_Supporting, PP4: Variant meets PM2 and is identified in 4 unrelated index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID 20809525, Marduel et al. 2010). PP1_Strong: Variant segregates with FH phenotype in at least 6 informative meioses from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France: 6 affected family members have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA037634/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 B:1
• Conservation: PhyloP100: 1.80

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 8 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.
• 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.1975A>C	p.Thr659Pro	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.1975A>C	p.Thr659Pro	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000547 AC: 8 AN: 1461820 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Benign:1

May 15, 2023

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.1975A>C (p.Thr659Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 15 May 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001853 (0.01853%) in European (Finnish) exomes (gnomAD v2.1.1). PS4_Supporting, PP4: Variant meets PM2 and is identified in 4 unrelated index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID 20809525, Marduel et al. 2010). PP1_Strong: Variant segregates with FH phenotype in at least 6 informative meioses from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France: 6 affected family members have the variant. -

Mar 30, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 4 , family members = 7 with co-segregation / previously described in association with FH/Software predictions: Conflicting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.57	D;.;.;.;.;.
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;D;T;T;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Uncertain	0.088	D
MutationAssessor	Benign	1.7	L;.;.;.;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.10	T;D;T;T;T;T
Sift4G	Benign	0.080	T;T;T;T;T;T
Polyphen		0.045	B;.;.;.;.;.
Vest4		0.36
MutPred		0.85		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;.;.;Loss of sheet (P = 0.0181);
MVP		1.0
MPC		0.37
ClinPred		0.063	T
GERP RS		4.3
Varity_R		0.76
gMVP		0.93

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: rs773693079; hg19: chr19-11230897;