rs745343524

Variant names:

• chr19-11113392-C-A
• rs745343524
• NM_000527.5:c.1301C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11113392-C-A
• chr19-11113392-C-G
• chr19-11113392-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5 PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met.PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon:- NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines- NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585392/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 B:1
• Conservation: PhyloP100: 1.05
• Publications: 12 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.
• PM5: 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.1301C>A	p.Thr434Lys	missense	Exon 9 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1301C>A	p.Thr434Lys	missense	Exon 9 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1178C>A	p.Thr393Lys	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.1301C>A	p.Thr434Lys	missense	Exon 9 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1559C>A	p.Thr520Lys	missense	Exon 9 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1301C>A	p.Thr434Lys	missense	Exon 9 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251262 AF XY: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727146

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: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	1	Hypercholesterolemia, familial, 1 (4)
1	-	-	Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.017	D
Sift4G	Benign	0.078	T
Polyphen		0.20	B
Vest4		0.37
MutPred		0.90		Loss of catalytic residue at T434 (P = 0.0047)
MVP		0.99
MPC		0.34
ClinPred		0.34	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.98
Mutation Taster		=4/96	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: rs745343524; hg19: chr19-11224068;