19-11113406-A-T

Variant names:

• chr19-11113406-A-T
• rs1057519670
• NM_000527.5:c.1315A>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):​c.1315A>T​(p.Asn439Tyr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N439K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.03
• Publications: 1 publications found

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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 32 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 19-11113406-A-T is Pathogenic according to our data. Variant chr19-11113406-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1315A>T	p.Asn439Tyr	missense	Exon 9 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1315A>T	p.Asn439Tyr	missense	Exon 9 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1192A>T	p.Asn398Tyr	missense	Exon 8 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1315A>T	p.Asn439Tyr	missense	Exon 9 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1573A>T	p.Asn525Tyr	missense	Exon 9 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1315A>T	p.Asn439Tyr	missense	Exon 9 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 , family member = 1 with unclear co-segregation (compound heterozygous associated with large rearrnagement) / Software predictions: Conflicting

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		1.0
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.077	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.67		Gain of relative solvent accessibility (P = 0.2363)
MVP		1.0
MPC		0.84
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519670; hg19: chr19-11224082;