19-11116989-C-A

Variant names:

• chr19-11116989-C-A
• rs143872778
• NM_000527.5:c.1836C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. BP7 PM2 BP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1836C>A (p.Ala612=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00015 (0.015%) in East Asian exomes and genomes (gnomAD v2.1.1).Frequency is higher in "other" population exomes and genomes but number of allele is below 10000BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.- Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT.- There is a GT nearby.MES scores: variant cryptic = -16.35, wt cryptic = -12.61, canonical donor = 4.48.Ratio variant cryptic/wt cryptic: -16.35/-12.61 = 1.30 --- it is above 1.1Ratio variant cryptic/canonical donor: -16.35/4.48 = -3.65 --- it is not above 0.9Variant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA036811/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 B:6
• Conservation: PhyloP100: -0.0330
• Publications: 5 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

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.1836C>A	p.Ala612Ala	synonymous	Exon 12 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1836C>A	p.Ala612Ala	synonymous	Exon 12 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1713C>A	p.Ala571Ala	synonymous	Exon 11 of 17	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.1836C>A	p.Ala612Ala	synonymous	Exon 12 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2094C>A	p.Ala698Ala	synonymous	Exon 12 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1836C>A	p.Ala612Ala	synonymous	Exon 12 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251468 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461852 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.000298 AC: 18 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.2
DANN	Benign	0.72
PhyloP100		-0.033
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs143872778; hg19: chr19-11227665;