19-11113728-A-G

Position:

• chr19-11113728-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1552A>G	p.Lys518Glu	missense_variant	10/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1552A>G	p.Lys518Glu	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	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 v4.3

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;T;T;T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.88	L;.;.;.;.;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.17	N;N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.23	B;.;.;.;.;.
Vest4		0.33
MutPred		0.84		Loss of MoRF binding (P = 0.0169);Loss of MoRF binding (P = 0.0169);.;.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254937; hg19: chr19-11224404;