chr19-11116926-CG-T

Variant names:

• chr19-11116926-CG-T
• rs1057519676
• NM_000527.5:c.1773_1774delCGinsT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000527.5(LDLR):​c.1773_1774delCGinsT​(p.Gly592AlafsTer72) variant causes a frameshift, synonymous 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. N591N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 frameshift, synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.86
• 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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 19-11116926-CG-T is Pathogenic according to our data. Variant chr19-11116926-CG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375823.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1773_1774delCGinsT	p.Gly592AlafsTer72	frameshift synonymous	Exon 12 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1773_1774delCGinsT	p.Gly592AlafsTer72	frameshift synonymous	Exon 12 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1650_1651delCGinsT	p.Gly551AlafsTer72	frameshift synonymous	Exon 11 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1773_1774delCGinsT	p.Gly592AlafsTer72	frameshift synonymous	Exon 12 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2031_2032delCGinsT	p.Gly678AlafsTer72	frameshift synonymous	Exon 12 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1773_1774delCGinsT	p.Gly592AlafsTer72	frameshift synonymous	Exon 12 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1

Familial hypercholesterolemia Pathogenic:1

Oct 28, 2025

GENinCode PLC

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1773_1774delinsT p.(Gly593AlafsTer72) frameshift variant is predicted to create a premature stop codon amino-terminal of amino acid 830 (PVS1_VERY STRONG) and is absent from gnomAD v4.1.0 (PM2_MODERATE). Based on the evidence listed above, we have classified this variant as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

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

Other links and lift over

dbSNP: rs1057519676; hg19: chr19-11227602;