NM_000527.5:c.669_683delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT

Variant names:

• chr19-11105575-GGACAAATCTGACGA-AACTGCGGTAAACTGCGGTAAACT
• rs1131692198
• NM_000527.5:c.669_683delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM4 PP2 PP3 PP5_Moderate

The NM_000527.5(LDLR):​c.669_683delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT​(p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu) variant causes a missense, disruptive inframe insertion 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 NM_000527.5 missense, disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.88
• Publications: 0 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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 50 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• 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: 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 VariationId is 430761.Status of the report is criteria_provided_single_submitter, 1 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.669_683delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT	p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu	missense disruptive_inframe_insertion	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.669_683delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT	p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu	missense disruptive_inframe_insertion	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.546_560delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT	p.Asp183_Glu187delinsThrAlaValAsnCysGlyLysLeu	missense disruptive_inframe_insertion	N/A	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.669_683delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT	p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu	missense disruptive_inframe_insertion	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.927_941delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT	p.Asp310_Glu314delinsThrAlaValAsnCysGlyLysLeu	missense disruptive_inframe_insertion	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.669_683delGGACAAATCTGACGAinsAACTGCGGTAAACTGCGGTAAACT	p.Asp224_Glu228delinsThrAlaValAsnCysGlyLysLeu	missense disruptive_inframe_insertion	N/A	ENSP00000453346.1

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

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

Other links and lift over

dbSNP: rs1131692198; hg19: chr19-11216251;