19-11113329-C-T

Variant names:

• chr19-11113329-C-T
• rs368562025
• NM_000527.5:c.1238C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PM2 PP1 PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Moderate, PP1 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 6 index cases.PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory.PP4 - Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023439/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:20 U:3
• Conservation: PhyloP100: 1.71
• Publications: 10 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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1238C>T	p.Thr413Met	missense	Exon 9 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1238C>T	p.Thr413Met	missense	Exon 9 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1115C>T	p.Thr372Met	missense	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.1238C>T	p.Thr413Met	missense	Exon 9 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1496C>T	p.Thr499Met	missense	Exon 9 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1238C>T	p.Thr413Met	missense	Exon 9 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000279 AC: 7 AN: 251176 AF XY: 0.0000442

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: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461564 Hom.: 1 Cov.: 33 AF XY: 0.0000413 AC XY: 30 AN XY: 727094

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112004

Other (OTH) AF: 0.0000994 AC: 6 AN: 60382

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.0000241 AC: 1 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

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

Alfa AF: 0.0000300 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	2	-	Hypercholesterolemia, familial, 1 (12)
5	-	-	not provided (5)
4	-	-	Familial hypercholesterolemia (4)
1	-	-	Cardiovascular phenotype (1)
-	1	-	Hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.65
MVP		1.0
MPC		0.80
ClinPred		0.78	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.96
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs368562025; hg19: chr19-11224005; COSMIC: COSV52944403; COSMIC: COSV52944403;