rs121908324

Variant names:

• chr1-25543763-G-A
• rs121908324
• NM_015627.3:c.65G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25543763-G-A
• chr1-25543763-G-C
• chr1-25543763-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015627.3(LDLRAP1):​c.65G>A​(p.Trp22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,208,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: LDLRAP1 NM_015627.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25543763-G-A is Pathogenic according to our data. Variant chr1-25543763-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25543763-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLRAP1	NM_015627.3	c.65G>A	p.Trp22*	stop_gained	Exon 1 of 9	ENST00000374338.5	NP_056442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.65G>A	p.Trp22*	stop_gained	Exon 1 of 9	1	NM_015627.3	ENSP00000363458.4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151672 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 25 AN: 1056872 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 9 AN XY: 498898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000408

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000484

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000239

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151672 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74100

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 4 Pathogenic:5

Sep 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4773). This premature translational stop signal has been observed in individual(s) with autosomal recessive hypercholesterolemia (PMID: 11326085). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp22*) in the LDLRAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLRAP1 are known to be pathogenic (PMID: 11326085, 12464675). -

May 18, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.75	D
Vest4		0.56
GERP RS		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121908324; hg19: chr1-25870254;