chr19-11113300-C-A

Position:

• chr19-11113300-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000527.5(LDLR):​c.1209C>A​(p.Phe403Leu) 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F403S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.32

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 14 ACMG points.

• PS1: Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 251732
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 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 chr19-11113299-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2568145.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 19-11113300-C-A is Pathogenic according to our data. Variant chr19-11113300-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 565474.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1209C>A	p.Phe403Leu	missense_variant	9/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1209C>A	p.Phe403Leu	missense_variant	9/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2019

A different variant (c.1207T>C) giving rise to the same protein effect observed here (p.Phe403Leu) has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15359125, 10447263), indicating that this residue may be critical for protein function. This variant is also known as p.Phe382Leu in the literature. For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant has been observed in an individual affected with hypercholesterolemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 565474). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 403 of the LDLR protein (p.Phe403Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.91	L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;T;D;D;D;D
Sift4G	Uncertain	0.038	D;D;T;T;T;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.49
MutPred		0.92		Loss of catalytic residue at H407 (P = 0.1222);Loss of catalytic residue at H407 (P = 0.1222);.;.;.;Loss of catalytic residue at H407 (P = 0.1222);
MVP		1.0
MPC		0.54
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs777903106; hg19: chr19-11223976;