Genetic Variant NM_000527.5:c.1957G>A (chr19-11120203-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM5PP2BP4

The NM_000527.5(LDLR):c.1957G>A(p.Val653Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V653G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.15

Publications

6 publications found

Variant links:

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

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000527.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11120204-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252130.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

BP4

Computational evidence support a benign effect (MetaRNN=0.3020963).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	NM_000527.5	MANE Select	c.1957G>A	p.Val653Ile	missense	Exon 13 of 18	NP_000518.1
LDLR	NM_001195798.2		c.1957G>A	p.Val653Ile	missense	Exon 13 of 18	NP_001182727.1
LDLR	NM_001195799.2		c.1834G>A	p.Val612Ile	missense	Exon 12 of 17	NP_001182728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1957G>A	p.Val653Ile	missense	Exon 13 of 18	ENSP00000454071.1
LDLR	ENST00000252444.10	TSL:1	c.2215G>A	p.Val739Ile	missense	Exon 13 of 18	ENSP00000252444.6
LDLR	ENST00000558013.5	TSL:1	c.1957G>A	p.Val653Ile	missense	Exon 13 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.0000656

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypercholesterolemia

Uncertain:2

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 653 of the LDLR protein (p.Val653Ile). This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 628891). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. This variant disrupts the p.Val653 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14974088, 30592178; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Apr 02, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant (also known as p.Val632Ile in the mature protein) is located in the sixth LDLR type B repeat of the 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 1/31398 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Hypercholesterolemia, familial, 1

Uncertain:1

Jun 28, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.30

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.65

PhyloP100

2.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.32

REVEL

Uncertain

0.37

Sift

Benign

0.47

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.097

MutPred

0.50

Loss of sheet (P = 0.0817)

MVP

0.96

MPC

0.18

ClinPred

0.25

GERP RS

4.3

Varity_R

0.17

gMVP

0.89

Mutation Taster

=41/59

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over