19-11120200-A-T

Position:

• chr19-11120200-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1954A>T	p.Met652Leu	missense_variant	13/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1954A>T	p.Met652Leu	missense_variant	13/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Aug 29, 2022

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 limits B) variant is exonic and at least 50bp upstream from canonical donor site, but does not create GT C) variant is exonic and there is no GT nearby Variant is not predicted to alter splicing. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Met631Leu in the mature protein) is located in the LDLR type B (YWTD) repeat 6 of EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-1.7	N;.;.;.;.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.53	N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.040	D;T;D;D;T;D
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.21
MutPred		0.64		Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);.;.;.;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

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: rs730882111; hg19: chr19-11230876;