rs5931

chr19-11089552-G-Achr19-11089552-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BP6_Strong

The NM_000527.5(LDLR):c.4G>A(p.Gly2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G2G) has been classified as Likely benign.

• 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-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15796185).
• BP6: Variant 19-11089552-G-A is Benign according to our data. Variant chr19-11089552-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 250970.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr19-11089552-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.4G>A	p.Gly2Arg	missense_variant	1/18	ENST00000558518.6
LDLR-AS1	NR_163945.1	n.108C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.4G>A	p.Gly2Arg	missense_variant	1/18	1	NM_000527.5	P3

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

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
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). -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

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
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.76	N;N;N;N;N;N
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;