rs879254779

Variant names:

• chr19-11111521-T-AGAGTGTCAGGATCCCGAC
• rs879254779
• NM_000527.5:c.1068delTinsAGAGTGTCAGGATCCCGAC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PM5

The NM_000527.5(LDLR):​c.1068delTinsAGAGTGTCAGGATCCCGAC​(p.Ile355_Asp356insGluGluCysGlnAspPro) variant causes a missense, conservative inframe insertion 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D356A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense, conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.48

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11111520-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1068delTinsAGAGTGTCAGGATCCCGAC	p.Ile355_Asp356insGluGluCysGlnAspPro	missense_variant, conservative_inframe_insertion	Exon 8 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1068delTinsAGAGTGTCAGGATCCCGAC	p.Ile355_Asp356insGluGluCysGlnAspPro	missense_variant, conservative_inframe_insertion	Exon 8 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

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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: rs879254779; hg19: chr19-11222197;