19-11116946-T-C

Variant names:

• chr19-11116946-T-C
• rs879255024
• NM_000527.5:c.1793T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1793T>C (p.Ile598Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specifications version 1.2) on 4 May 2023.The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meet PM2. PMID:20809525 (Marduel et al., 2010), France – at least 1 case who fulfills internationally accepted criteria for FH, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585615/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 7.87
• Publications: 7 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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: 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.1793T>C	p.Ile598Thr	missense	Exon 12 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1793T>C	p.Ile598Thr	missense	Exon 12 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1670T>C	p.Ile557Thr	missense	Exon 11 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.1793T>C	p.Ile598Thr	missense	Exon 12 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2051T>C	p.Ile684Thr	missense	Exon 12 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1793T>C	p.Ile598Thr	missense	Exon 12 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2

May 04, 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.1793T>C (p.Ile598Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specifications version 1.2) on 4 May 2023. The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - Variant meet PM2. PMID: 20809525 (Marduel et al., 2010), France – at least 1 case who fulfills internationally accepted criteria for FH, after alternative causes of high cholesterol were excluded.

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0010	B
Vest4		0.65
MutPred		0.85		Loss of stability (P = 0.0037)
MVP		1.0
MPC		0.28
ClinPred		0.78	D
GERP RS		5.5
Varity_R		0.51
gMVP		0.96
Mutation Taster		=0/100	disease causing

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: rs879255024; hg19: chr19-11227622;