19-11110739-G-T

Position:

• chr19-11110739-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3 PM5_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1028G>T (p.Gly343Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5_Strong) 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).PP3: REVEL=0.983, it is above 0.75.PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met.PP4, PS4 not met: Variant meets PM2, and is reported in 1 index case, but the FH diagnosis and clinical information for the patient is not clear, reported by Miyake et al, 2009, National Cardiovascular Center Research Institute, Osaka, Japan, PMID18718593.PS3 not met: Functional data is not available. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404082758/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.65

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1028G>T	p.Gly343Val	missense_variant	7/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1028G>T	p.Gly343Val	missense_variant	7/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5 (LDLR):c.1028G>T (p.Gly343Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5_Strong) 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). PP3: REVEL=0.983, it is above 0.75. PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met. PP4, PS4 not met: Variant meets PM2, and is reported in 1 index case, but the FH diagnosis and clinical information for the patient is not clear, reported by Miyake et al, 2009, National Cardiovascular Center Research Institute, Osaka, Japan, PMID18718593. PS3 not met: Functional data is not available. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.4	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-8.7	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.96
MutPred		0.98		Loss of catalytic residue at G343 (P = 0.1781);Loss of catalytic residue at G343 (P = 0.1781);.;.;.;Loss of catalytic residue at G343 (P = 0.1781);
MVP		1.0
MPC		0.89
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
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: rs879254760; hg19: chr19-11221415;