chr19-11105575-GGACAAATCTGACGA-AACTGCGGTAAACTGCGGTAAACT

Position:

• chr19-11105575-GGACAAATCTGACGA-AACTGCGGTAAACTGCGGTAAACT

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The ENST00000558518.6(LDLR):​c.669_683delinsAACTGCGGTAAACTGCGGTAAACT​(p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu) variant causes a protein altering change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K223K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR ENST00000558518.6 protein_altering
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.88

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 9 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in ENST00000558518.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000558518.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-11105575-GGACAAATCTGACGA-AACTGCGGTAAACTGCGGTAAACT is Pathogenic according to our data. Variant chr19-11105575-GGACAAATCTGACGA-AACTGCGGTAAACTGCGGTAAACT is described in ClinVar as [Pathogenic]. Clinvar id is 430761.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.669_683delinsAACTGCGGTAAACTGCGGTAAACT	p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu	protein_altering_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.669_683delinsAACTGCGGTAAACTGCGGTAAACT	p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu	protein_altering_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 30, 2017

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131692198; hg19: chr19-11216251;