19-11105566-CGACTGCAAGGACAAATCT-CGACTGCAAGGACAAATCTGACTGCAAGGACAAATCT

Variant names:

• chr19-11105566-C-CGACTGCAAGGACAAATCT
• rs387906306
• NM_000527.5:c.664_681dupTGCAAGGACAAATCTGAC

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):​c.664_681dupTGCAAGGACAAATCTGAC​(p.Cys222_Asp227dup) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,334 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 conservative_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.88
• Publications: 7 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 13 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
• 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 19-11105566-C-CGACTGCAAGGACAAATCT is Pathogenic according to our data. Variant chr19-11105566-C-CGACTGCAAGGACAAATCT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.664_681dupTGCAAGGACAAATCTGAC	p.Cys222_Asp227dup	conservative_inframe_insertion	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.664_681dupTGCAAGGACAAATCTGAC	p.Cys222_Asp227dup	conservative_inframe_insertion	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250012 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459334 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725552

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110528

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Apr 16, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys222_Asp227dup variant in LDLR (also known as FH Padua-4l) has been reported in 5 families with hypercholesterolemia, occured de novo in 1 of these individuals, and segregated with disease in at least 1 affected relative (Bertolini 2000, Chmara 2010, Giesel 1995, Kotze 1995, Pavanello 2019). This variant has also been identified in 1/12968 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 3733). This variant is an insertion of 6 amino acids at position 222 and is not predicted to alter the protein reading-frame. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PM6, PM2, PS4_Moderate. -

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

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 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Familial hypercholesterolemia Pathogenic:2

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.664_681dup, results in the insertion of 6 amino acid(s) of the LDLR protein (p.Cys222_Asp227dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs387906306, gnomAD 0.0009%). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 7581403, 7649546, 10978268, 20145306). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.201-206dup and CKDKSD206–207ins. ClinVar contains an entry for this variant (Variation ID: 3733). For these reasons, this variant has been classified as Pathogenic. -

May 07, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM2, PM4, PS2:Moderate, PS4:Moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=33/67	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs387906306; hg19: chr19-11216242;