19-11113660-TGG-T

Variant names:

• chr19-11113660-TGG-T
• rs869025454
• NM_000527.5:c.1486_1487delGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.1486_1487delGG​(p.Gly496HisfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.63
• 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]

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11113660-TGG-T is Pathogenic according to our data. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113660-TGG-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 222689.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.1486_1487delGG	p.Gly496HisfsTer39	frameshift_variant	Exon 10 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1486_1487delGG	p.Gly496HisfsTer39	frameshift_variant	Exon 10 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 11, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Pathogenic:1

Apr 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 222689). This sequence change creates a premature translational stop signal (p.Gly496Hisfs*39) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 11810272). This variant is also known as 1486delGG or the Surinam allele. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869025454; hg19: chr19-11224336;