19-11105585-GACG-GCGGTATGGACTGCA

Position:

• chr19-11105585-GACG-GCGGTATGGACTGCA

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_682delACGinsCGGTATGGACTGCA​(p.Asp227fs) 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:5
• 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-CGGTATGGACTGCA is Pathogenic according to our data. Variant chr19-11105586-ACG-CGGTATGGACTGCA is described in ClinVar as [Pathogenic]. Clinvar id is 422951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.680_682delACGinsCGGTATGGACTGCA	p.Asp227fs	frameshift_variant, missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.680_682delACGinsCGGTATGGACTGCA	p.Asp227fs	frameshift_variant, missense_variant	4/18	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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2025	Very similar insertion/deletion (c.679del4ins15; originally reported as 676insACGGTATGGACTGCAdelGACG), has been identified in one individual with primary hypercholesterolemia in the published literature (PMID: 11462246); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.Asp207AlafsX; This variant is associated with the following publications: (PMID: 17539906, 31447099, 32770674, 27535533, 11462246, 28161202) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 07, 2023	The LDLR c.680_682delins14 (p.Asp227Alafs*42) variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature in individuals with definite or suspected familial hypercholesterolemia (PMIDs: 17539906 (2007), 26802169 (2016), 28161202 (2017), 29572815 (2018), and 32770674 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hypercholesterolemia, familial, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 16, 2024

This variant deletes 3 nucleotides and inserts 14 nucleotides in exon 4 of the LDLR type A repeat 5 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 26802169, 28161202, 29888156, 29572815, 32770674). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2018

The c.680_682delACGins14 pathogenic mutation, located in coding exon 4 of the LDLR gene, results from the deletion of 3 nucleotides and insertion of 14 nucleotides (CGGTATGGACTGCA) at positions 680 to 682, causing a translational frameshift with a predicted alternate stop codon (p.D227Afs*42). This mutation has been previously reported in two familial hypercholesterolemia cohorts (Taylor A et al. Clin. Genet. 2007:71(6):561-8; Minicocci I et al. Pediatr. 2017;183:100-107). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 19, 2019

Variant summary: LDLR c.680_682delins14 (c.680_682delinsCGGTATGGACTGCA, p.Asp227AlafsX42) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248472 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Marmontel_2018, Taylor_2007, Wintjens_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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;