rs1064792905

chr19-11105586-ACGAGGAAAACTG-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):c.683_694del(p.Glu228_Cys231del) variant causes a inframe deletion, splice region 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. D227D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 inframe_deletion, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.88

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 Pathogenic. Variant got 15 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
• 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 19-11105586-ACGAGGAAAACTG-A is Pathogenic according to our data. Variant chr19-11105586-ACGAGGAAAACTG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 403633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.683_694del	p.Glu228_Cys231del	inframe_deletion, splice_region_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.683_694del	p.Glu228_Cys231del	inframe_deletion, splice_region_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Nov 05, 2016

Disrupt SDE motif. SDE bind structural Ca2+. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2018

The c.683_694del12 variant (also known as p.E228_C231del) is located in coding exon 4 of the LDLR gene. This variant results from an in-frame AGGAAAACTGCG deletion at nucleotide positions 683 to 694 at the end of exon 4. This results in the deletion of four amino acids between codons 228 and 231. This alteration has been reported in a cohort of subjects with familial hypercholesterolemia (Tichý L et al. Physiol Res, 2017 Apr;66:S47-S54). In addition, internal structural analysis indicates that this alteration both alters the conserved SDE triplet motif and disrupts a disulfide bond in the LDL type A repeat 5, which is important for ligand binding (Ambry internal data). Based on four different splice site prediction tools, this alteration is expected to create an in-frame alternate splice donor site at the new exon-intron boundary created by the deletion; however, experimental evidence is not currently available. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 21, 2017

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. For these reasons, this variant has been classified as Pathogenic. At least two different substitutions within this deleted sequence (p.Gln228Gln and p.Cys231Gly) have been determined to be pathogenic (PMID: 8882879, 16250003, 17094996, 8664907). This suggests that several residues within this region are critical for LDLR protein function. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This sequence change deletes 12 nucleotides from exon 4 of the LDLR mRNA (c.683_694delAGGAAAACTGCG). This leads to the deletion of 4 amino acid residues in the LDLR protein (p.Glu228_Cys231del) but otherwise preserves the integrity of the reading frame. -

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: rs1064792905; hg19: chr19-11216262;