19-11120166-C-T

Position:

• chr19-11120166-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BA1 BS3_Supporting BP4 BP7

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1920C>T (p.Asn640=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BP4, BP7, BS3_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:BA1: FAF=0.03838 in Ashkenazi Jewish population in gnomAD (gnomAD 2.1.1).BP4: No REVEL, splicing evaluation required. A) not in limit. B) does not create AG or GT. C) there is a GT nearby. Var cryptic score/Wt cryptic score=0.69, it is not above 1.1, and Var cryptic score/Wt score= -0.80, it is not above 0.9. Variant is not predicted to alter splicing.BP7: Variant is synonymous and meets BP4.BS3_Supporting: Level 3 assay with heterozygous patients’ lymphocytes, RNA assays shown normal LDLR transcripts, reported by Medeiros et al, 2016, from Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal, PMID 26020417. Functional data is consistent with no damaging effect.PP4, PS4 not met: Variant did not meet PM2.PP1 not met: There are 2 relatives without the variant had LDL-C <50th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BS4 not met: There are 2 relatives without the variant had LDL-C >75th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, and there is no instance where an unaffected family member carries the variant, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.BP2 not met: Variant identified in an index case with heterozygous FH phenotype and an unspecified LDLR variant with unknown pathogenicity and phase, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. LINK:https://erepo.genome.network/evrepo/ui/classification/CA037448/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (27 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:3 B:17
• Conservation: PhyloP100: -1.67

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 Benign. Variant got -11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1920C>T	p.Asn640=	synonymous_variant	13/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1920C>T	p.Asn640=	synonymous_variant	13/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 484 AN: 152166 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00436 AC: 1096 AN: 251492 Hom.: 5 AF XY: 0.00448 AC XY: 609 AN XY: 135920

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00368

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00303 AC: 4424 AN: 1461720 Hom.: 27 Cov.: 33 AF XY: 0.00313 AC XY: 2279 AN XY: 727182

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.0355

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000881

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00603

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152284 Hom.: 5 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74468

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00326

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00576 Hom.: 1

Bravo AF: 0.00301

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00450

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:17

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:3 Benign:7

Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	does not meet required criteria -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jan 27, 2023	The NM_000527.5 (LDLR):c.1920C>T (p.Asn640=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BP4, BP7, BS3_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: BA1: FAF=0.03838 in Ashkenazi Jewish population in gnomAD (gnomAD 2.1.1). BP4: No REVEL, splicing evaluation required. A) not in limit. B) does not create AG or GT. C) there is a GT nearby. Var cryptic score/Wt cryptic score=0.69, it is not above 1.1, and Var cryptic score/Wt score= -0.80, it is not above 0.9. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. BS3_Supporting: Level 3 assay with heterozygous patients’ lymphocytes, RNA assays shown normal LDLR transcripts, reported by Medeiros et al, 2016, from Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal, PMID 26020417. Functional data is consistent with no damaging effect. PP4, PS4 not met: Variant did not meet PM2. PP1 not met: There are 2 relatives without the variant had LDL-C <50th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BS4 not met: There are 2 relatives without the variant had LDL-C >75th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, and there is no instance where an unaffected family member carries the variant, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 not met: Variant identified in an index case with heterozygous FH phenotype and an unspecified LDLR variant with unknown pathogenicity and phase, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/95 non-FH individuals -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LDLR: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 07, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial hypercholesterolemia Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 20, 2022	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.34
DANN	Benign	0.91

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: rs5926; hg19: chr19-11230842;