1-25543763-G-C

Variant names:

Variant summary

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

The NM_015627.3(LDLRAP1):c.65G>C(p.Trp22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,208,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. W22R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000066 ( 0 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

Publications

6 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:

Genome browser will be placed here

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLRAP1	NM_015627.3 link	c.65G>C	p.Trp22Ser	missense_variant	Exon 1 of 9	ENST00000374338.5	NP_056442.2	Q5SW96B3KR97

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LDLRAP1	ENST00000374338.5 link	c.65G>C	p.Trp22Ser	missense_variant	Exon 1 of 9	1	NM_015627.3	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000718277.1 link	c.65G>C	p.Trp22Ser	missense_variant	Exon 1 of 10			ENSP00000520715.1
LDLRAP1	ENST00000718287.1 link	c.65G>C	p.Trp22Ser	missense_variant	Exon 1 of 6			ENSP00000520725.1
LDLRAP1	ENST00000718288.1 link	n.65G>C		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000520726.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000662

AC:

AN:

1056876

Hom.:

Cov.:

AF XY:

0.00000601

AC XY:

AN XY:

498900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22000

American (AMR)

AF:

0.00

AC:

AN:

7620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13142

East Asian (EAS)

AF:

0.0000408

AC:

AN:

24532

South Asian (SAS)

AF:

0.000103

AC:

AN:

19358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2854

European-Non Finnish (NFE)

AF:

0.00000332

AC:

AN:

904862

Other (OTH)

AF:

0.0000239

AC:

AN:

41846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151780

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41500

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67842

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Sep 18, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W22S variant (also known as c.65G>C), located in coding exon 1 of the LDLRAP1 gene, results from a G to C substitution at nucleotide position 65. The tryptophan at codon 22 is replaced by serine, an amino acid with highly dissimilar properties. This variant has been detected in a myocardial infarction cohort; however, details were not provided (Lee C et al. Lipids Health Dis, 2019 Apr;18:95). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.0091

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.75

Eigen

Benign

0.060

Eigen_PC

Benign

0.036

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.2

PhyloP100

3.2

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.37

MutPred

0.47

Gain of glycosylation at W22 (P = 0.0098);

MVP

0.66

MPC

0.32

ClinPred

0.99

GERP RS

3.0

PromoterAI

0.016

Neutral

(source)

Varity_R

0.79

gMVP

0.51

Mutation Taster

=17/83

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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1-25543763-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over