rs879254626

Variant names:

• chr19-11105573-A-AAGGACAAATCTG
• rs879254626
• NM_000527.5:c.669_680dupGGACAAATCTGA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_000527.5(LDLR):​c.669_680dupGGACAAATCTGA​(p.Ser226_Asp227insGluAspLysSer) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D227D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.101
• Publications: 2 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 12 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000527.5
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PP5: Variant 19-11105573-A-AAGGACAAATCTG is Pathogenic according to our data. Variant chr19-11105573-A-AAGGACAAATCTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251369.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.669_680dupGGACAAATCTGA	p.Ser226_Asp227insGluAspLysSer	disruptive_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.669_680dupGGACAAATCTGA	p.Ser226_Asp227insGluAspLysSer	disruptive_inframe_insertion	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame substitution of 2 amino acids at codons 226 to 227 with 4 novel amino acids in the LDLR protein protein (p.Ser226_Asp227insGluAspLysSer). This variant alters a conserved aspartic acid residue in the LDLR type A repeat 5 of the LDLR protein (a.a. 195-232), where pathogenic missense variants are found enriched (ClinVar-LDLR). This substitution introduces the variant p.Asp227Glu, which is known to be disease-causing (ClinVar variation ID: 3690). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least seven individuals affected with familial hypercholesterolemia (PMID: 11139254, 14974088, 20145306, 32770674, 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Apr 15, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4_MOD,PM2,PM4 -

Familial hypercholesterolemia Pathogenic:3

Jul 09, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.669_680dup12 (p.Ser226_Asp227insGluAspLysSer) results in an in-frame insertion that is predicted to insert 4 amino acids (EDKS) into the encoded protein. The variant was absent in 245680 control chromosomes. c.669_680dup12 has been reported in the literature in individuals affected with Familial Hypercholesterolemia, indicating that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mar 28, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame substitution of 2 amino acids at codons 226 to 227 with 4 novel amino acids in the LDLR protein protein (p.Ser226_Asp227insGluAspLysSer). This variant alters a conserved aspartic acid residue in the LDLR type A repeat 5 of the LDLR protein (a.a. 195-232), where pathogenic missense variants are found enriched (ClinVar-LDLR). This substitution introduces the variant p.Asp227Glu, which is known to be disease-causing (ClinVar variation ID: 3690). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least seven individuals affected with familial hypercholesterolemia (PMID: 11139254, 14974088, 20145306, 32770674, 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Nov 03, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a rare in-frame duplication that is absent from population controls and has has been observed in several affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acid is currently unknown. This variant has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID: 11139254, 20145306, Invitae database). This variant is also known as p.K202_D203insDKSE in the literature. ClinVar contains an entry for this variant (Variation ID: 251369). This variant is not present in population databases (ExAC no frequency). This sequence change inserts 12 nucleotides in exon 4 of the LDLR mRNA (c.669_680dupGGACAAATCTGA). This leads to the insertion of 4 amino acid residue(s) in the LDLR protein (p.Ser226_Asp227insGluAspLysSer) but otherwise preserves the integrity of the reading frame. -

LDLR-related disorder Pathogenic:1

Jul 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LDLR c.669_680dup12 variant is predicted to result in an in-frame duplication (p.Ser226_Asp227insGluAspLysSer). This variant has been reported in multiple individuals with hypercholesterolemia (Bochmann et al. 2000. PubMed ID: 11139254; Chmara et al. 2010. PubMed ID: 20145306; Sturm et al. 2021. PubMed ID: 34037665. eTable 1). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.10
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879254626; hg19: chr19-11216249;