rs878854024

Positions:

• chr19-11111549-CAGCTCTGCGTGA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000527.5(LDLR):​c.1098_1109del​(p.Gln366_Asn370delinsHis) variant causes a inframe deletion 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.77

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 19-11111549-CAGCTCTGCGTGA-C is Pathogenic according to our data. Variant chr19-11111549-CAGCTCTGCGTGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237862.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1098_1109del	p.Gln366_Asn370delinsHis	inframe_deletion	8/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1098_1109del	p.Gln366_Asn370delinsHis	inframe_deletion	8/18	1	NM_000527.5	P3

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:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2023

This variant, c.1098_1109del, is a complex sequence change that results in the deletion of 5 and insertion of 1 amino acid(s) in the LDLR protein (p.Gln366_Asn370delinsHis). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 237862). This variant disrupts a region of the LDLR protein in which other variant(s) (p.Cys368Tyr) have been determined to be pathogenic (PMID: 1301940, 15241806, 16314194, 21722902). 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. -

Hypercholesterolemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2016

This sequence change deletes 12 nucleotides from exon 8 of the LDLR mRNA (c.1098_1109delGCTCTGCGTGAA). This leads to the replacement of 5 amino acid residues by a non-related one in the LDLR protein (p.Gln366_Asn370delinsHis) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a LDLR-related disease. This variant is located in EGF-like B domain of the LDLR protein and deletes a cysteine (p.Cys368) that is suggested to be involved in the formation of a disulfide bridge (PMID: 3282918, 3495735, 4750422). A missense substitution at this codon (p.Cys368Tyr) is reported to be deleterious (PMID: 1301940, 15241806, 16314194, 21722902). This indicates that the p.Cys368 residue is important for LDLR protein function. In summary, this is a novel in-frame deletion that may affect protein function. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. -

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: rs878854024; hg19: chr19-11222225;