rs879254460

Positions:

• chr19-11102772-A-G
• chr19-11102772-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3 PP1 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.299A>G (p.Asp100Gly) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PP4, PS4_supporting 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).- PP1: variant segregates with FH phenotype in 3 informative meiosis in 1 family from Laboratory of Genetics and Molecular Cardiology: 2 relatives with the phenotype and the variant and 1 relative without the phenotype and without the variant.- PP3: REVEL = 0.9.- PP4: Variant meets PM2 and is identified in at least 1 index case (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID:11810272 clinically diagnosed with definite heterozygous FH), after alternative causes of high cholesterol were excluded.- PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID:11810272 clinically diagnosed with definite heterozygous FH) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584833/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.28

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 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.299A>G	p.Asp100Gly	missense_variant	3/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.299A>G	p.Asp100Gly	missense_variant	3/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.299A>G (p.Asp100Gly) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PP4, PS4_supporting 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). - PP1: variant segregates with FH phenotype in 3 informative meiosis in 1 family from Laboratory of Genetics and Molecular Cardiology: 2 relatives with the phenotype and the variant and 1 relative without the phenotype and without the variant. - PP3: REVEL = 0.9. - PP4: Variant meets PM2 and is identified in at least 1 index case (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH), after alternative causes of high cholesterol were excluded. - PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH) -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
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	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.2	H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.1	D;D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.78
MutPred		0.91		Gain of glycosylation at S99 (P = 0.0167);Gain of glycosylation at S99 (P = 0.0167);Gain of glycosylation at S99 (P = 0.0167);Gain of glycosylation at S99 (P = 0.0167);Gain of glycosylation at S99 (P = 0.0167);
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs879254460; hg19: chr19-11213448;