rs777512182

Variant names:

• chr19-11105604-TGGGCGGGGCCA-T
• rs777512182
• NM_000527.5:c.694+8_694+18delCGGGGCCAGGG

Your query was ambiguous. Multiple possible variants found:

• chr19-11105604-TGGGCGGGGCCA-T
• chr19-11105604-TGGGCGGGGCCA-TGGGCGGGGCCAGGGCGGGGCCA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000527.5(LDLR):​c.694+8_694+18delCGGGGCCAGGG variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000526 in 1,006,926 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000053 (1 hom.)
• Consequence: LDLR NM_000527.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 8.22
• Publications: 1 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 19-11105604-TGGGCGGGGCCA-T is Benign according to our data. Variant chr19-11105604-TGGGCGGGGCCA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 630368.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.694+8_694+18delCGGGGCCAGGG		splice_region intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.694+8_694+18delCGGGGCCAGGG		splice_region intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.571+8_571+18delCGGGGCCAGGG		splice_region intron	N/A	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.694+5_694+15delGGGCGGGGCCA		splice_region intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.952+5_952+15delGGGCGGGGCCA		splice_region intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.694+5_694+15delGGGCGGGGCCA		splice_region intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000780 AC: 19 AN: 243694 AF XY: 0.000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000526 AC: 53 AN: 1006926 Hom.: 1 AF XY: 0.0000788 AC XY: 40 AN XY: 507892

African (AFR) AF: 0.00 AC: 0 AN: 23278

American (AMR) AF: 0.00 AC: 0 AN: 39246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18300

East Asian (EAS) AF: 0.00 AC: 0 AN: 22408

South Asian (SAS) AF: 0.000637 AC: 50 AN: 78456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 745290

Other (OTH) AF: 0.0000751 AC: 3 AN: 39930

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Familial hypercholesterolemia (3)
-	2	-	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypercholesterolemia, familial, 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.2
Mutation Taster		=14/86	disease causing

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs777512182;

hg19: chr19-11216280;