rs879254637

Variant names:

• chr19-11105586-ACG-CA
• rs879254637
• NM_000527.5:c.680_682delACGinsCA

Your query was ambiguous. Multiple possible variants found:

• chr19-11105585-GACG-GCA
• chr19-11105585-GACG-GCGGTATGGACTGCA
• chr19-11105585-GACG-GNNNNNNNNNNNNNN

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.680_682delACGinsCA​(p.Asp227AlafsTer38) variant causes a frameshift, missense 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D227D?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 frameshift, missense
• Clinical Significance: 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 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 19-11105586-ACG-CA is Pathogenic according to our data. Variant chr19-11105586-ACG-CA is described in ClinVar as [Pathogenic]. Clinvar id is 430762.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.680_682delACGinsCA	p.Asp227AlafsTer38	frameshift_variant, missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.680_682delACGinsCA	p.Asp227AlafsTer38	frameshift_variant, missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

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

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:2

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asp227Alafs*38) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 26802169). For these reasons, this variant has been classified as Pathogenic. -

Jun 25, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant replaces three nucleotides in exon 4 of the LDLR gene with two new nucleotides, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a French individual affected with hypercholesterolemia (PMID: 26802169). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Hypercholesterolemia, familial, 1 Pathogenic:1

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs879254637; hg19: chr19-11216262;