rs879255150

chr19-11123183-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_000527.5(LDLR):c.2150C>G(p.Ala717Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A717T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.632

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 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-11123183-C-G is Benign according to our data. Variant chr19-11123183-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252242.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr19-11123183-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2150C>G	p.Ala717Gly	missense_variant	15/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2150C>G	p.Ala717Gly	missense_variant	15/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
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	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	14
Dann	Benign	0.80
DEOGEN2	Uncertain	0.48	T;.;.;.;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.60	T;T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	N;.;.;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.85	N;N;N;N;N;N
Sift	Benign	0.21	T;T;T;T;T;T
Sift4G	Benign	0.17	T;D;T;T;T;T
Polyphen		0.018	B;.;.;.;.;.
Vest4		0.47
MutPred		0.72		Loss of stability (P = 0.0666);Loss of stability (P = 0.0666);.;.;.;Loss of stability (P = 0.0666);
MVP		1.0
MPC		0.22
ClinPred		0.060	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.67

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: rs879255150; hg19: chr19-11233859;