chr19-11105575-G-GGACAAATCT

Variant names:

• chr19-11105575-G-GGACAAATCT
• rs1555803425
• NM_000527.5:c.673_681dupAAATCTGAC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):​c.673_681dupAAATCTGAC​(p.Lys225_Asp227dup) variant causes a conservative 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E228E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 conservative_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.88
• 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]

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 15 ACMG points.

• PM1: In a hotspot region, there are 42 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-11105575-G-GGACAAATCT is Pathogenic according to our data. Variant chr19-11105575-G-GGACAAATCT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 251377.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.673_681dupAAATCTGAC	p.Lys225_Asp227dup	conservative_inframe_insertion	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.673_681dupAAATCTGAC	p.Lys225_Asp227dup	conservative_inframe_insertion	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.550_558dupAAATCTGAC	p.Lys184_Asp186dup	conservative_inframe_insertion	Exon 3 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.673_681dupAAATCTGAC	p.Lys225_Asp227dup	conservative_inframe_insertion	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.931_939dupAAATCTGAC	p.Lys311_Asp313dup	conservative_inframe_insertion	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.673_681dupAAATCTGAC	p.Lys225_Asp227dup	conservative_inframe_insertion	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

May 24, 2021

Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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 = 2 , family member = 1

Familial hypercholesterolemia Pathogenic:1

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.673_681dup, results in the insertion of 3 amino acid(s) of the LDLR protein (p.Lys225_Asp227dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypercholesterolemia (PMID: 15477777, 15556093, 20809525, 31491741, 34297352). This variant is also known as c681insAAATCTGAC, c.671_679dup (Dup204K-206D). ClinVar contains an entry for this variant (Variation ID: 251377). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555803425; hg19: chr19-11216251;