19-11116989-C-T

Position:

• chr19-11116989-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP7 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1836C>T (p.Ala612=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence code BP4 and BP7 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:BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.- Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT.- There is a GT nearby.MES scores: variant cryptic = -16.82, wt cryptic = -12.61, canonical donor = 4.48.Ratio variant cryptic/wt cryptic: -16.82/-12.61 = 1.33 --- it is above 1.1Ratio variant cryptic/canonical donor: -16.82/4.48 = -3.75 --- it is not above 0.9Variant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA036837/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:4 B:11
• Conservation: PhyloP100: -0.0330

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_benign. Variant got -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1836C>T	p.Ala612=	synonymous_variant	12/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1836C>T	p.Ala612=	synonymous_variant	12/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251468 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135904

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000316

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000233 AC: 340 AN: 1461848 Hom.: 0 Cov.: 34 AF XY: 0.000256 AC XY: 186 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74302

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.000162

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:4 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2015	MAF =<0.3%, LDL-C >=160 mg/dL -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.1836C>T (p.Ala612=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence code BP4 and BP7 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: BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. - Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. - There is a GT nearby. MES scores: variant cryptic = -16.82, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.82/-12.61 = 1.33 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.82/4.48 = -3.75 --- it is not above 0.9 Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.1836C>T (p.Ala612Ala) variant has been reported in two studies and is found in a total of eight familial hypercholesterolemia patients in a heterozygous state (Widhalm et al. 2007; Chmara et al. 2010). In silico analysis of this variant predicted no effect on consensus splice sites and overall non-pathogenicity (Chmara et al. 2010; Usifo et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00034 in the European (Non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Ala612Ala variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial hypercholesterolemia. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 22, 2022	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2019	This variant is associated with the following publications: (PMID: 22881376, 28145427, 17347910, 20145306, 32719484) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LDLR: BP4, BP7 -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2023	Variant summary: LDLR c.1836C>T alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 251468 control chromosomes (i.e., 46 heterozygotes; gnomAD v2.1 Exomes dataset). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease (0.00018 vs 0.001), allowing no conclusion about variant significance. The variant, c.1836C>T, has been reported in the literature in individuals affected with premature atherosclerosis and/or hypercholesterolaemia (e.g., Widhalm_2007, Chmara_2010, Saracoglu_2018). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 28145427, 22881376, 17347910, 29870584). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (benign, n = 1; likely benign, n = 5; VUS, n = 4; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is a silent variant in LDLR. It is classified as DM in HGMD. This variant has been reported in 7 patients with familial hypercholesterolemia in one study (Widhalm 2007). This variant is classified in ClinVar with 1 star as VUS by Mayo Clinic and as Likely Benign by British Heart Foundation. The variant has a Max MAF of 0.03% in ExAC (23 alleles) and 0.03% in gnomAD (43 alleles). -

Familial hypercholesterolemia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

LDLR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2021

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	-0.34
CADD	Benign	9.9
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs143872778; hg19: chr19-11227665;