rs879254617

Variant names:

• chr19-11105560-TGGCCCC-T
• rs879254617
• NM_000527.5:c.656_661delGCCCCG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_000527.5(LDLR):​c.656_661delGCCCCG​(p.Gly219_Pro220del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G219G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 1.94
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 45 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PP5: Variant 19-11105560-TGGCCCC-T is Pathogenic according to our data. Variant chr19-11105560-TGGCCCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 251353.

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.656_661delGCCCCG	p.Gly219_Pro220del	disruptive_inframe_deletion	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.656_661delGCCCCG	p.Gly219_Pro220del	disruptive_inframe_deletion	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.533_538delGCCCCG	p.Gly178_Pro179del	disruptive_inframe_deletion	Exon 3 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.656_661delGCCCCG	p.Gly219_Pro220del	disruptive_inframe_deletion	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.914_919delGCCCCG	p.Gly305_Pro306del	disruptive_inframe_deletion	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.656_661delGCCCCG	p.Gly219_Pro220del	disruptive_inframe_deletion	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457010 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 724506

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109508

Other (OTH) AF: 0.00 AC: 0 AN: 60072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Hypercholesterolemia, familial, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879254617; hg19: chr19-11216236;