chr19-11113589-AGACATCCAGGCCCCC-A

Variant names:

• chr19-11113589-AGACATCCAGGCCCCC-A
• rs879254893
• NM_000527.5:c.1417_1431delATCCAGGCCCCCGAC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP5_Moderate

The NM_000527.5(LDLR):​c.1417_1431delATCCAGGCCCCCGAC​(p.Ile473_Asp477del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.87
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 18 uncertain in NM_000527.5
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PP5: Variant 19-11113589-AGACATCCAGGCCCCC-A is Pathogenic according to our data. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113589-AGACATCCAGGCCCCC-A is described in CliVar as Likely_pathogenic. Clinvar id is 251831.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1417_1431delATCCAGGCCCCCGAC	p.Ile473_Asp477del	conservative_inframe_deletion	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.1417_1431delATCCAGGCCCCCGAC	p.Ile473_Asp477del	conservative_inframe_deletion	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879254893; hg19: chr19-11224265;