19-11113728-A-G

Variant names:

• chr19-11113728-A-G
• rs879254937
• NM_000527.5:c.1552A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP4 PP1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1552A>G (p. Lys518Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP1) 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: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for Definite FH after alternative causes of high cholesterol were excluded, from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation. PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family: 1 affected relative tested positive and 1 unaffected relative tested negative for the variant, reported from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation.PP3 not met: REVEL = 0.593, it is not above 0.75, splicing evaluation required. Variant is exonic and is not on limit creating de novo acceptor site. It is located at least 50bp downstream from canonical acceptor site but does not create GT. Variant is not predicted to alter splicing.PS3 not met: Functional data is not available for this variant.PS4 not met: Variant meets PM2 and is identified in less than 2 index case who fulfil FH diagnosis criteria. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.1553A>G (p.Lys518Arg) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585499/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 3.36
• Publications: 4 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 4 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1552A>G	p.Lys518Glu	missense	Exon 10 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1552A>G	p.Lys518Glu	missense	Exon 10 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1429A>G	p.Lys477Glu	missense	Exon 9 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1552A>G	p.Lys518Glu	missense	Exon 10 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1810A>G	p.Lys604Glu	missense	Exon 10 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1552A>G	p.Lys518Glu	missense	Exon 10 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

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: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

Apr 28, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5 (LDLR):c.1552A>G (p. Lys518Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP1) 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: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for Definite FH after alternative causes of high cholesterol were excluded, from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation. PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family: 1 affected relative tested positive and 1 unaffected relative tested negative for the variant, reported from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation. PP3 not met: REVEL = 0.593, it is not above 0.75, splicing evaluation required. Variant is exonic and is not on limit creating de novo acceptor site. It is located at least 50bp downstream from canonical acceptor site but does not create GT. Variant is not predicted to alter splicing. PS3 not met: Functional data is not available for this variant. PS4 not met: Variant meets PM2 and is identified in less than 2 index case who fulfil FH diagnosis criteria. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.1553A>G (p.Lys518Arg) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Benign	0.66
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.88	L
PhyloP100		3.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.59
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.23	B
Vest4		0.33
MutPred		0.84		Loss of MoRF binding (P = 0.0169)
MVP		1.0
MPC		0.45
ClinPred		0.28	T
GERP RS		3.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.41
gMVP		0.98
Mutation Taster		=3/97	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: rs879254937; hg19: chr19-11224404;