19-11120200-A-T

Variant names:

• chr19-11120200-A-T
• rs730882111
• NM_000527.5:c.1954A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1954A>T (p.Met652Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 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 follow:PM2_Met : the variant was absent from controls in Gnomad database (gnomAD v2.1.1).BP4_Met : REVEL score is 0.252, splicing evaluation required.Functional data on splicing not available.A) Variant not on limitsB) variant is exonic and at least 50bp upstream from canonical donor site, but does not create GTC) variant is exonic and there is no GT nearbyVariant is not predicted to alter splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404093163/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 3.24
• Publications: 1 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.1954A>T	p.Met652Leu	missense	Exon 13 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1954A>T	p.Met652Leu	missense	Exon 13 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1831A>T	p.Met611Leu	missense	Exon 12 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1954A>T	p.Met652Leu	missense	Exon 13 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2212A>T	p.Met738Leu	missense	Exon 13 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1954A>T	p.Met652Leu	missense	Exon 13 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.62
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-1.7	N
PhyloP100		3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.25
Sift	Benign	0.040	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.64		Loss of sheet (P = 0.302)
MVP		0.95
MPC		0.20
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.23
gMVP		0.88
Mutation Taster		=68/32	polymorphism

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: rs730882111; hg19: chr19-11230876;