19-11120113-A-T

Variant names:

• chr19-11120113-A-T
• NM_000527.5:c.1867A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000527.5(LDLR):​c.1867A>T​(p.Ile623Phe) 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. I623T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.108

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11120114-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1867A>T	p.Ile623Phe	missense_variant	Exon 13 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1867A>T	p.Ile623Phe	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Uncertain:1

Apr 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 30971288; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 623 of the LDLR protein (p.Ile623Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	D;.;.;.;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.9	L;.;.;.;.;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.13	T;T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T
Polyphen		0.54	P;.;.;.;.;.
Vest4		0.49
MutPred		0.67		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);.;.;.;Loss of loop (P = 0.0986);
MVP		1.0
MPC		0.86
ClinPred		0.50	T
GERP RS		-0.48
Varity_R		0.38
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11230789;