Genetic Variant LDLRAP1:p.Arg151Gly (chr1-25557259-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015627.3(LDLRAP1):c.451C>G(p.Arg151Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.71

Publications

7 publications found

Variant links:

Genes affected

LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]

LDLRAP1 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLRAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015627.3. 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
	LDLRAP1	NM_015627.3	MANE Select	c.451C>G	p.Arg151Gly	missense	Exon 4 of 9	NP_056442.2	Q5SW96

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLRAP1	ENST00000374338.5	TSL:1 MANE Select	c.451C>G	p.Arg151Gly	missense	Exon 4 of 9	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000894925.1		c.514C>G	p.Arg172Gly	missense	Exon 5 of 10	ENSP00000564984.1
LDLRAP1	ENST00000894924.1		c.451C>G	p.Arg151Gly	missense	Exon 4 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445896

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719842

African (AFR)

AF:

0.00

AC:

AN:

33206

American (AMR)

AF:

0.00

AC:

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

39230

South Asian (SAS)

AF:

0.00

AC:

AN:

85982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099234

Other (OTH)

AF:

0.00

AC:

AN:

59726

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.8

PhyloP100

1.7

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.23

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

0.23

Vest4

0.78

MutPred

0.45

Loss of MoRF binding (P = 0.0199)

MVP

0.76

MPC

0.34

ClinPred

0.98

GERP RS

4.8

Varity_R

0.87

gMVP

0.54

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over