rs759858813

chr19-11120482-C-Gchr19-11120482-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Strong

The NM_000527.5(LDLR):c.2100C>G(p.Asp700Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D700G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: -2.54

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 Pathogenic. Variant got 12 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, 12 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11120481-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252220.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 19-11120482-C-G is Pathogenic according to our data. Variant chr19-11120482-C-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 252221.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr19-11120482-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2100C>G	p.Asp700Glu	missense_variant	14/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2100C>G	p.Asp700Glu	missense_variant	14/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 25, 2022	The NM_000527.5(LDLR):c.2100C>G (p.Asp700Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting and PP4 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), so PM2 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill SB criteria for FH from Malaysia (PMID: 21418584), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Benign	0.079
Dann	Benign	0.96
DEOGEN2	Uncertain	0.78	D;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.6
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T;T;D;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.9	L;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.093	T;T;T;T;T
Polyphen		0.99	D;.;.;.;.
Vest4		0.68
MutPred		0.73		Gain of solvent accessibility (P = 0.1376);Gain of solvent accessibility (P = 0.1376);.;.;Gain of solvent accessibility (P = 0.1376);
MVP		0.99
MPC		0.78
ClinPred		0.94	D
GERP RS		-11
Varity_R		0.46
gMVP		0.87

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: rs759858813; hg19: chr19-11231158;