chr19-11113504-GCGCTGATG-CGGCT

Position:

• chr19-11113504-GCGCTGATG-CGGCT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS3_Supporting PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:- PM2: This variant is absent from gnomAD (gnomAD v2.1.1).- PP4: Variant meets PM2. Identified in 1 FH case from PMID:8872473 meeting Simon-Broome criteria of possible FH , after alternative causes of high cholesterol were excluded.- PS3: Level 3 assay: PMID 8872473:Heterozygous patient's Epstein-Barr virus transformed lymphoblasts, RNA assays; Heterologous cells (COS), RNA assays: Retention of intron 9 (p.Ser453Argfs*2)---- functional study is consistent with damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585420/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 29)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:3 B:1
• Conservation: PhyloP100: 1.53

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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1359-31_1359-23delinsCGGCT		intron_variant		ENST00000558518.6
MIR6886	NR_106946.1	n.31_39delinsCGGCT		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1359-31_1359-23delinsCGGCT		intron_variant		1	NM_000527.5	P3
MIR6886	ENST00000619864.1	n.31_39delinsCGGCT		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 29

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

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2 Benign:1

Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 20, 2023	The NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: This variant is absent from gnomAD (gnomAD v2.1.1). - PP4: Variant meets PM2. Identified in 1 FH case from PMID: 8872473 meeting Simon-Broome criteria of possible FH , after alternative causes of high cholesterol were excluded. - PS3: Level 3 assay: PMID 8872473: Heterozygous patient's Epstein-Barr virus transformed lymphoblasts, RNA assays; Heterologous cells (COS), RNA assays: Retention of intron 9 (p.Ser453Argfs*2) ---- functional study is consistent with damaging effect. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2018

The c.1359-31_1359-23delGCGCTGATGinsCGGCT intronic variant, located in intron 9 of the LDLR gene, results from an in-frame from the deletion of 9 nucleotides and the insertion of 5 nucleotides at nucleotide position 1359. This alteration has been reported in an individual with familial hypercholesterolemia (FH), and RNA studies have demonstrated that this alteration leads to the retention of intron 9 and incorporation of a premature stop codon (Webb JC et al. Hum. Mol. Genet., 1996 Sep;5:1325-31). These nucleotide positions are not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 25, 2023

This variant deletes 9 nucleotides and inserts 5 nucleotides, CGGCT, in intron 9 of the LDLR gene. An RNA study using patient-derived lymphoblasts and a minigene assay have shown that this variant causes a retention of intron 9 sequence in mRNA and utilization of cryptic acceptor sites in exon 10, resulting in a frameshift and premature translation stop signal (PMID: 8872473). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 8872473). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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: rs879254876; hg19: chr19-11224180;