chr19-11129520-CGTCTTCCTTTGCCTGGGG-C

Position:

• chr19-11129520-CGTCTTCCTTTGCCTGGGG-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_000527.5(LDLR):​c.2407_2424delTGCCTGGGGGTCTTCCTT​(p.Cys803_Leu808del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 4.94

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PP5: Variant 19-11129520-CGTCTTCCTTTGCCTGGGG-C is Pathogenic according to our data. Variant chr19-11129520-CGTCTTCCTTTGCCTGGGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438330.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2407_2424delTGCCTGGGGGTCTTCCTT	p.Cys803_Leu808del	conservative_inframe_deletion	17/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2407_2424delTGCCTGGGGGTCTTCCTT	p.Cys803_Leu808del	conservative_inframe_deletion	17/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 26, 2019	- -

LDLR-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

The LDLR c.2407_2424del18 variant is predicted to result in an in-frame deletion (p.Cys803_Leu808del). This variant has been reported in the heterozygous state in four individuals with hypercholesterolemia (Leren et al. 2021. PubMed ID: 33740630. Table S1). In vitro functional analysis suggests that this deletion may reduce protein level (Strøm et al. 2015. PubMed ID: 26220972). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This variant, c.2407_2424del, results in the deletion of 6 amino acid(s) of the LDLR protein (p.Cys803_Leu808del), 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 familial hypercholesterolemia (PMID: 33740630). ClinVar contains an entry for this variant (Variation ID: 438330). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 26220972). This variant disrupts a region of the LDLR protein in which other variant(s) (p.Gly805Arg) have been determined to be pathogenic (PMID: 15199436, 24918045, 33740630). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.2407_2424del18 variant (also known as p.C803_L808del) is located in coding exon 17 of the LDLR gene. This variant results from an in-frame TGCCTGGGGGTCTTCCTT deletion at nucleotide positions 2407 to 2424. This results in the in-frame deletion of the amino acids at codons 803 to 808. An in vitro assay showed this alteration may impact protein function (Strøm TB et al. Hum Mol Genet, 2015 Oct;24:5836-44). This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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: rs879255201; hg19: chr19-11240196;