chr19-11089552-G-A

Position:

• chr19-11089552-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.4G>A (p.Gly2Arg) variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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 - Variant is absent from gnomAD (gnomAD v2.1.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584722/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: 0.301

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]

LDLR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: 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.4G>A	p.Gly2Arg	missense_variant	1/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.4G>A	p.Gly2Arg	missense_variant	1/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

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	Mar 08, 2022	NM_000527.5(LDLR):c.4G>A (p.Gly2Arg) variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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 - Variant is absent from gnomAD (gnomAD v2.1.1). -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	8.5
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T;.;.;.;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T;T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.90	L;.;L;L;L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.76	N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.47	T;D;T;T;T;T
Sift4G	Benign	0.11	T;D;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.14
MutPred		0.55		Loss of catalytic residue at G2 (P = 0.0368);Loss of catalytic residue at G2 (P = 0.0368);Loss of catalytic residue at G2 (P = 0.0368);Loss of catalytic residue at G2 (P = 0.0368);Loss of catalytic residue at G2 (P = 0.0368);Loss of catalytic residue at G2 (P = 0.0368);
MVP		0.92
MPC		0.25
ClinPred		0.063	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.034
gMVP		0.70

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: rs5931; hg19: chr19-11200228;