19-11128070-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM1 PM2 PM5 PP3_Strong BP6_Strong

The NM_000527.5(LDLR):c.2374A>T(p.Ile792Phe) 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. I792T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 0.360

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 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 chr19-11128071-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• BP6: Variant 19-11128070-A-T is Benign according to our data. Variant chr19-11128070-A-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 252294.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr19-11128070-A-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2374A>T	p.Ile792Phe	missense_variant	16/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2374A>T	p.Ile792Phe	missense_variant	16/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2 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	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 26, 2022	The NM_000527.5 (LDLR):c.2374A>T (p. Ile792Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) 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). PP3: REVEL = 0.764. PS3_Moderate not met: Level 2 experiment, heterologous cells (HepG2) were used for western blot and immunoprecipitation assays showed normal cell surface LDLR, reported by Strøm et al, 2015, (PMID 26220972), Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics and Department of Microbiology and Bioinformatics Core Facility, University of Oslo and Oslo University Hospital, Oslo, Norway. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2375T>C (p.Ile792Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.83	D;.;.;.;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D;T;D;D;T;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D;N;D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.95	P;.;.;.;.;.
Vest4		0.51
MutPred		0.83		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;.;.;Gain of helix (P = 0.0425);
MVP		1.0
MPC		0.35
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.20
gMVP		0.95

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: rs761123215; hg19: chr19-11238746;