rs781585299

chr1-25563135-A-ACchr1-25563135-A-ACC

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.603dup(p.Ser202LeufsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,609,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T200T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: LDLRAP1 NM_015627.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.44

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25563135-A-AC is Pathogenic according to our data. Variant chr1-25563135-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 4781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLRAP1	NM_015627.3	c.603dup	p.Ser202LeufsTer19	frameshift_variant	6/9	ENST00000374338.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.603dup	p.Ser202LeufsTer19	frameshift_variant	6/9	1	NM_015627.3	P1
LDLRAP1	ENST00000484476.5	n.325dup		non_coding_transcript_exon_variant	1/4	1
LDLRAP1	ENST00000488127.1	n.1073dup		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150866 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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1458710 Hom.: 0 Cov.: 31 AF XY: 0.0000400 AC XY: 29 AN XY: 725780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000602

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150866 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73568

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: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 4 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	This sequence change creates a premature translational stop signal (p.Ser202Leufs*19) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 12464675, 12788851, 21872251, 22157599). It has also been observed to segregate with disease in related individuals. This variant is also known as insC620. ClinVar contains an entry for this variant (Variation ID: 4781). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Dec 10, 2021

- -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs781585299; hg19: chr1-25889626;