rs879255023

Positions:

• chr19-11116945-A-C
• chr19-11116945-A-G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1792A>C (p.Ile598Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and BP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meet PM2. PMID:11810272 (Fouchier et al., 2001), Netherlands - et least 1 case who fulfills validated clinical criteria for FH.BP4 - REVEL: 0.487, it is below 0.50, splicing evaluation required.Functional data on splicing not available.Scenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons.Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical splicing site of any exons.Scenario B, Acceptor site: The variant is located within the range but does not create de novo AG site.Scenario B, Donor site: The variant is located within range but does not create de novo GT site.Scenario C, Acceptor site: The variant is located at -20 to +3 bases of intraexonic AG but AG is not within the range.Scenario C, Donor site: The variant is not located at -3 to +6 bases of intraexonic GTInterpretation: The variant does not affect splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585613/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 B:1
• Conservation: PhyloP100: -0.715

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.1792A>C	p.Ile598Leu	missense_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.1792A>C	p.Ile598Leu	missense_variant	12/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, 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	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.1792A>C (p.Ile598Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and BP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - Variant meet PM2. PMID: 11810272 (Fouchier et al., 2001), Netherlands - et least 1 case who fulfills validated clinical criteria for FH. BP4 - REVEL: 0.487, it is below 0.50, splicing evaluation required. Functional data on splicing not available. Scenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons. Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical splicing site of any exons. Scenario B, Acceptor site: The variant is located within the range but does not create de novo AG site. Scenario B, Donor site: The variant is located within range but does not create de novo GT site. Scenario C, Acceptor site: The variant is located at -20 to +3 bases of intraexonic AG but AG is not within the range. Scenario C, Donor site: The variant is not located at -3 to +6 bases of intraexonic GT Interpretation: The variant does not affect splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	0.021
DANN	Benign	0.41
DEOGEN2	Uncertain	0.57	D;.;.;.;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.55	T;T;T;T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-0.11	N;.;.;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.57	N;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.79	T;T;T;T;T;T
Sift4G	Benign	0.97	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.29
MutPred		0.84		Gain of ubiquitination at K603 (P = 0.0719);Gain of ubiquitination at K603 (P = 0.0719);.;.;.;Gain of ubiquitination at K603 (P = 0.0719);
MVP		0.87
MPC		0.21
ClinPred		0.028	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.94

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: rs879255023; hg19: chr19-11227621;