rs879255075

Positions:

• chr19-11120174-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. BP4 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1928C>T (p.Ala643Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).BP4: REVEL = 0.481; score is below 0.50, splicing evaluation required. A). Not on limits.B). it creates a GT. Variant is exonic and at least 50bp upstream/downstream from canonical donor/acceptor site and creates a de novo GT. MES scores: variant cryptic site = -9.79, WT cryptic site = -17.54, canonical donor site= 10.28. De novo score is negative, so it is not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon-Broome criteria for FH (PMID 20809525) after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585683/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 B:1
• Conservation: PhyloP100: 1.04

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.1928C>T	p.Ala643Val	missense_variant	13/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1928C>T	p.Ala643Val	missense_variant	13/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jul 02, 2024	The NM_000527.5(LDLR):c.1928C>T (p.Ala643Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). BP4: REVEL = 0.481; score is below 0.50, splicing evaluation required. A). Not on limits. B). it creates a GT. Variant is exonic and at least 50bp upstream/downstream from canonical donor/acceptor site and creates a de novo GT. MES scores: variant cryptic site = -9.79, WT cryptic site = -17.54, canonical donor site= 10.28. De novo score is negative, so it is not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon-Broome criteria for FH (PMID 20809525) after alternative causes of high cholesterol were excluded. -
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 benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 02, 2019

This missense variant (also known as p.Ala622Val in the mature protein) is located in the sixth LDLR type B repeat in the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a French individual affected with hypercholesterolemia (PMID: 20809525). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.7	L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N;N;D;D;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.29	T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.013	B;.;.;.;.;.
Vest4		0.16
MutPred		0.57		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;.;.;Loss of loop (P = 0.0374);
MVP		1.0
MPC		0.30
ClinPred		0.23	T
GERP RS		3.3
Varity_R		0.41
gMVP		0.89

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: rs879255075; hg19: chr19-11230850;