19-11113285-C-T

Variant names:

• chr19-11113285-C-T
• rs13306498
• NM_000527.5:c.1194C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP7 BS1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows:BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1).BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.Variant is not located within the limits of canonical splicing sitesVariant is exonic and at least 50bp upstream from canonical donor site but does not creates AGThere is no AG NearbyVariant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA033001/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel P:1 B:16
• Conservation: PhyloP100: -1.08
• Publications: 7 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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1194C>T	p.Ile398Ile	synonymous	Exon 9 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1194C>T	p.Ile398Ile	synonymous	Exon 9 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1071C>T	p.Ile357Ile	synonymous	Exon 8 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.1194C>T	p.Ile398Ile	synonymous	Exon 9 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1452C>T	p.Ile484Ile	synonymous	Exon 9 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1194C>T	p.Ile398Ile	synonymous	Exon 9 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 235 AN: 152080 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00174 AC: 437 AN: 250716 AF XY: 0.00167

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00533

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00119 AC: 1745 AN: 1460576 Hom.: 17 Cov.: 33 AF XY: 0.00117 AC XY: 849 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.000157 AC: 7 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0174 AC: 690 AN: 39700

South Asian (SAS) AF: 0.000615 AC: 53 AN: 86200

European-Finnish (FIN) AF: 0.0108 AC: 571 AN: 53028

Middle Eastern (MID) AF: 0.000394 AC: 2 AN: 5074

European-Non Finnish (NFE) AF: 0.000326 AC: 362 AN: 1111960

Other (OTH) AF: 0.000945 AC: 57 AN: 60304

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152198 Hom.: 1 Cov.: 29 AF XY: 0.00206 AC XY: 153 AN XY: 74398

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.000197 AC: 3 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5178

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000496 Hom.: 0

Bravo AF: 0.000623

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	6	Hypercholesterolemia, familial, 1 (7)
-	-	4	not provided (4)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant familial hypercholesterolemia (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.4
DANN	Benign	0.76
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13306498; hg19: chr19-11223961; COSMIC: COSV52944512; COSMIC: COSV52944512;