19-11120201-T-C

Position:

• chr19-11120201-T-C

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and PS4_Supporting 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: PopMax = 0.00005 in East Asians (gnomAD v2.1.1).PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfil clinical criteria for FH: 1 patient with DLCN >6 from the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI); 1 patient with Simon Broome = Definite FH (PMID:20236128).PP1_Strong: Variant segregates with the FH phenotype in 8 informative meioses from 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI): 5 affected family members have the variant and 3 non-affected family members do not have the variant.PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH (Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA, Australia; VCI), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576326/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:3
• Conservation: PhyloP100: 7.85

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1955T>C	p.Met652Thr	missense_variant	13/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1955T>C	p.Met652Thr	missense_variant	13/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:1

Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 25, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 29, 2022	The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and PS4_Supporting 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 follow: PM2_ Met : Allele frequency is 0.00005 (18394 alleles) in the East Asian subpopulation in GnomAD (gnomAD v2.1.1). PP4_Met : 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA - as defined by DLCN>6 and 1 from PMID: 20236128 as defined by Simon Broome score = definite). PS4_Supporting: 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA -with DLCN>6 and 1 from PMID: 20236128 with Simon Broome score = definite) and 1 case with untreated LDL-C=348 (Ambry Genetics). PMID:20829525 1 carrier was identified but the FH phenotype was evaluated only considering total and LDL-cholesterol levels above the 95 th percentile when compared with a sex- and age-matched French population. I will not consider this patient. PMID:22883975 1 carrier with clinical FH defined by DLCN score was reported. However, it is impossible to understand if the patient carrying the variant has a DLCN>6. I will not consider this patient. PMID: 28964736 1 carrier with clinical FH was reported in the cohort of ALTERNATIVE study which did not have a recorded diagnosis of FH, as they had very high baseline LDL-C levels (>5.0 mmol/L, ∼193 mg/dL).No data on FH its FC classification is reported. I will not consider this patient. PP1_Strong : Variant segregates with phenotype in 5 relatives in 1 family. (8 informative meiosis) -

Familial hypercholesterolemia Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 26, 2020	This missense variant (also known as p.Met631Thr in the mature protein) replaces methionine with threonine at codon 652 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 20236128, 20809525, 22883975, 28964736). It has been shown that this variant segregates with disease in one family (Al-Olabi et al 2019). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 652 of the LDLR protein (p.Met652Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 28964736; Invitae). ClinVar contains an entry for this variant (Variation ID: 226382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The p.M652T variant (also known as c.1955T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide position 1955. The methionine at codon 652 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Defesche JC et al. J Clin Lipidol, 2017 Sep;11:1338-1346.e7; Ajufo E et al. Genet Med, 2021 Sep;23:1697-1704). (Meshkov A et al. Genes (Basel), 2021 Jan;12; Ambry internal data). Internal structural analysis indicates this variant to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8). Additionally, an in vitro assay showed this alteration had a reduction of LDL uptake (Larrea-Sebal A et al. JACC Basic Transl Sci, 2021 Nov;6:815-827). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.55	N;.;.;.;.;N
MutationTaster	Benign	0.82	D;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.0060	B;.;.;.;.;.
Vest4		0.38
MutPred		0.68		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);
MVP		1.0
MPC		0.59
ClinPred		0.63	D
GERP RS		4.3
Varity_R		0.70
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs875989936; hg19: chr19-11230877;