GeneBe

chr1-25563135-A-ACC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_015627.3(LDLRAP1):​c.602_603dupCC​(p.Ser202ProfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,926 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S202S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LDLRAP1
NM_015627.3 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

Publications

9 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRAP1NM_015627.3 linkc.602_603dupCC p.Ser202ProfsTer3 frameshift_variant Exon 6 of 9 ENST00000374338.5 NP_056442.2 Q5SW96B3KR97

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRAP1ENST00000374338.5 linkc.602_603dupCC p.Ser202ProfsTer3 frameshift_variant Exon 6 of 9 1 NM_015627.3 ENSP00000363458.4 Q5SW96

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1458926
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
725886
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33460
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26100
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39674
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86222
European-Finnish (FIN)
AF:
0.0000188
AC:
1
AN:
53234
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1109500
Other (OTH)
AF:
0.00
AC:
0
AN:
60284
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs781585299; hg19: chr1-25889626; COSMIC: COSV100974805; COSMIC: COSV100974805; API