rs879254459

Variant names:

• chr19-11102771-G-A
• rs879254459
• NM_000527.5:c.298G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3 PM2 PP3 PP4 PP1 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, 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)- PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C=10.25 mmol/L ) as homozygous status, from PMID:25936346.- PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID:25936346- PP3: REVEL = 0.93- PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH from Ambry Genetics, after alternative causes for high cholesterol were excluded.- PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of possible FH from Ambry Genetics, 1 cases with Simon-Broome criteria of possible FH from PMID:25936346) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584832/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 8.06
• Publications: 2 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.298G>A	p.Asp100Asn	missense	Exon 3 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.298G>A	p.Asp100Asn	missense	Exon 3 of 18	NP_001182727.1
	LDLR	NM_001195800.2		c.298G>A	p.Asp100Asn	missense	Exon 3 of 16	NP_001182729.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.298G>A	p.Asp100Asn	missense	Exon 3 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.556G>A	p.Asp186Asn	missense	Exon 3 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.298G>A	p.Asp100Asn	missense	Exon 3 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000436 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Hypercholesterolemia, familial, 1 (4)
1	-	-	Cardiovascular phenotype (1)
-	1	-	Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		8.1
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.93		Loss of phosphorylation at S99 (P = 0.2526)
MVP		1.0
MPC		0.79
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs879254459; hg19: chr19-11213447;