19-11110738-G-T

Position:

• chr19-11110738-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1_Strong PM2 PP3 PP4 PM5 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1027G>T (p.Gly343Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PP1_Strong, PM5, PM3) 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 in gnomAD (gnomAD v2.1.1).PP3: REVEL=0.92, it is above 0.75.PP4: Variant meets PM2 and is identified in 1 index case who fulfil criteria for FH after alternative causes of high cholesterol were excluded. The patient had LDL-C level of 16.62 mmol/L with xanthomas and CHD, reported by Jelassi et al, 2009 and 2010, from Research Unit of Genetic and Biologic Factors of Atherosclerosis, Faculty of Medicine, Monastir, Tunisia, PMID 18757057 and 20144596. PP1_Strong: Variant segregates with FH phenotype in 6 informative meiosis from 1 family: 5 affected relatives were positive, 1 unaffected relative was negative for the variant, reported by Jelassi et al, PMID 18757057 and 20144596.PM5: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5 is met.PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype with plasma LDL-C 16.62 mmol/L, reported by Jelassi et al, PMID 18757057. This variant met enough pathogenic criteria toward Pathogenic classification by these guidelines before PM3 code applied.PS4 not met: Variant meets PM2 and is reported in 1 index case fulfil FH criteria and with homozygous FH phenotype, by Jelassi et al, PMID 18757057 and 20144596.PS3 not met: Functional data is not available. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585257/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: 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]

LDLR (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.1027G>T	p.Gly343Cys	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.1027G>T	p.Gly343Cys	missense_variant	7/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5 (LDLR):c.1027G>T (p.Gly343Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PP1_Strong, PM5, PM3) 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 in gnomAD (gnomAD v2.1.1). PP3: REVEL=0.92, it is above 0.75. PP4: Variant meets PM2 and is identified in 1 index case who fulfil criteria for FH after alternative causes of high cholesterol were excluded. The patient had LDL-C level of 16.62 mmol/L with xanthomas and CHD, reported by Jelassi et al, 2009 and 2010, from Research Unit of Genetic and Biologic Factors of Atherosclerosis, Faculty of Medicine, Monastir, Tunisia, PMID 18757057 and 20144596. PP1_Strong: Variant segregates with FH phenotype in 6 informative meiosis from 1 family: 5 affected relatives were positive, 1 unaffected relative was negative for the variant, reported by Jelassi et al, PMID 18757057 and 20144596. PM5: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5 is met. PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype with plasma LDL-C 16.62 mmol/L, reported by Jelassi et al, PMID 18757057. This variant met enough pathogenic criteria toward Pathogenic classification by these guidelines before PM3 code applied. PS4 not met: Variant meets PM2 and is reported in 1 index case fulfil FH criteria and with homozygous FH phenotype, by Jelassi et al, PMID 18757057 and 20144596. PS3 not met: Functional data is not available. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;.;.;.;.;H
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-8.7	D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.97
MutPred		0.98		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;.;.;Loss of sheet (P = 0.1907);
MVP		1.0
MPC		0.83
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
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: rs730882096; hg19: chr19-11221414;