19-11111639-G-C

Position:

• chr19-11111639-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, 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).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for definite/possible FH after alternative causes of high cholesterol were excluded. Reported by Miroshnikova et al, National Research Center ”Kurchatov Institute”, Gatchina, Russian Federation, PMID 33269076. PP3: REVEL= 0.702, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. The variant is predicted affecting splicing process in scenario A, donor site: The variant is located at -3 to +6 bases of canonical donor splicing site of exon 8. Wild type canonical donor motif: TGGGTGAGC, MES: 7.23 Variant canonical donor motif: TGCGTGAGC, MES: 3.45. Var/Wt ratio = 0.48, (< 0.8), met PP3.PS3 not met: Functional data not available.PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630). None is classified as Pathogenic by these guidelines, therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404083996/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 4.98

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1186G>C	p.Gly396Arg	missense_variant, splice_region_variant	8/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1186G>C	p.Gly396Arg	missense_variant, splice_region_variant	8/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Oct 28, 2022	The NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, 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). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD version 2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for definite/possible FH after alternative causes of high cholesterol were excluded. Reported by Miroshnikova et al, National Research Center ”Kurchatov Institute”, Gatchina, Russian Federation, PMID 33269076. PP3: REVEL= 0.702, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. The variant is predicted affecting splicing process in scenario A, donor site: The variant is located at -3 to +6 bases of canonical donor splicing site of exon 8. Wild type canonical donor motif: TGGGTGAGC, MES: 7.23 Variant canonical donor motif: TGCGTGAGC, MES: 3.45. Var/Wt ratio = 0.48, (< 0.8), met PP3. PS3 not met: Functional data not available. PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630). None is classified as Pathogenic by these guidelines, therefore PM5 is not met. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Human Molecular Genetics, Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC "Kurchatov Institute"	Feb 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.56
MutPred		0.57		Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);.;.;.;Gain of MoRF binding (P = 0.0179);
MVP		1.0
MPC		0.87
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.72
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: -4
DS_DL_spliceai		0.34		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879254820; hg19: chr19-11222315;