rs879254586

Positions:

• chr19-11105505-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000527.5(LDLR):​c.599T>G​(p.Phe200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F200I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: -0.803

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.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11105505-T-G is Pathogenic according to our data. Variant chr19-11105505-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251314.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.599T>G	p.Phe200Cys	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.599T>G	p.Phe200Cys	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2023

This variant is also known as F179C. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20538126, 30592178, 33994402). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 200 of the LDLR protein (p.Phe200Cys). ClinVar contains an entry for this variant (Variation ID: 251314). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe200 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

LDLR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2023

The LDLR c.599T>G variant is predicted to result in the amino acid substitution p.Phe200Cys. This variant is also described using legacy nomenclature as p.Phe179Cys, has been reported in individuals with Hypercholesterolemia (Chiou et al. 2010. PubMed ID: 20538126; Chan et al. 2018. PubMed ID: 30592178. Table S1; Huang et al. 2021. PubMed ID: 33994402). Different missense variants in the same codon (p.Phe200Leu; p.Phe200Ile) have been reported in individuals with Hypercholesterolemia (Nauck et al. 2001. PubMed ID: 11462246; ClinVar ID: 251313). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypercholesterolemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Uncertain	0.59	D;.;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.0	L;.;.;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.10	T;T;T;T
Sift4G	Uncertain	0.059	T;T;T;T
Polyphen		0.80	P;.;.;.
Vest4		0.35
MutPred		0.54		Gain of disorder (P = 0.0458);Gain of disorder (P = 0.0458);.;Gain of disorder (P = 0.0458);
MVP		1.0
MPC		0.83
ClinPred		0.27	T
GERP RS		0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.24
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879254586; hg19: chr19-11216181;