rs879254759

chr19-11110733-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PM1 PM2 PP3_Strong BP6_Moderate

The NM_000527.5(LDLR):c.1022C>G(p.Pro341Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P341P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.67

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• BP6: Variant 19-11110733-C-G is Benign according to our data. Variant chr19-11110733-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 251602.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11110733-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.1022C>G	p.Pro341Arg	missense_variant	7/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1022C>G	p.Pro341Arg	missense_variant	7/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Likely benign, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;.;.;.
Eigen	Benign	0.0082
Eigen_PC	Benign	0.078
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.66	N;.;.;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D
Sift	Benign	0.085	T;T;T;T;D;T
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.44	B;.;.;.;.;.
Vest4		0.85
MutPred		0.84		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;.;.;Loss of sheet (P = 0.1907);
MVP		1.0
MPC		0.42
ClinPred		0.58	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.99

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: rs879254759; hg19: chr19-11221409;