rs755154048

Variant names:

• chr19-11113705-C-T
• rs755154048
• NM_000527.5:c.1529C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.1529C>T (p.Thr510Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002228 (0.002228%) in East Asian exomes (gnomAD v4.1.0). PP3 - REVEL = 0.85. PS4_supporting, PP4: Variant meets PM2 and was identified in 4 unrelated index cases (1 case with DLCN score >=6 from Robarts Research Institute, Canada; 1 case meeting Simon Broome criteria from PMID 10947889 (Tonstad et al., 2000), Norway; 1 case with possible FH by MedPed criteria from PMID 22698793 (Tichý et al., 2012), Czech Republic; 1 case with clinical diagnosis of definite FH, probable FH or severe hypercholesterolemia according to the Canadian definition of FH from PMID 37607748 (Guerin et al., 2023), Canada]. LINK:https://erepo.genome.network/evrepo/ui/classification/CA034662/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:9
• Conservation: PhyloP100: 4.07
• 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]

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: Uncertain_significance. The variant received 5 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.
• PP3: 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.1529C>T	p.Thr510Met	missense	Exon 10 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1529C>T	p.Thr510Met	missense	Exon 10 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1406C>T	p.Thr469Met	missense	Exon 9 of 17	NP_001182728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1529C>T	p.Thr510Met	missense	Exon 10 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1787C>T	p.Thr596Met	missense	Exon 10 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1529C>T	p.Thr510Met	missense	Exon 10 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251450 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727240

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111998

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000289 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	4	-	Hypercholesterolemia, familial, 1 (6)
-	3	-	Familial hypercholesterolemia (3)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.85
Sift	Benign	0.090	T
Sift4G	Benign	0.068	T
Polyphen		0.93	P
Vest4		0.46
MutPred		0.84		Gain of MoRF binding (P = 0.0673)
MVP		1.0
MPC		0.78
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.31
gMVP		0.90
Mutation Taster		=2/98	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: rs755154048; hg19: chr19-11224381; COSMIC: COSV99369612; COSMIC: COSV99369612;