NM_015627.3(LDLRAP1):c.112_113del (p.Thr38fs) AND Hypercholesterolemia, familial, 4

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 14, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001386372.7

Allele description [Variation Report for NM_015627.3(LDLRAP1):c.112_113del (p.Thr38fs)]

NM_015627.3(LDLRAP1):c.112_113del (p.Thr38fs)

Gene:

LDLRAP1:low density lipoprotein receptor adaptor protein 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

1p36.11

Genomic location:

Preferred name:

NM_015627.3(LDLRAP1):c.112_113del (p.Thr38fs)

HGVS:

NC_000001.11:g.25553943AC[1]
NC_000001.11:g.25553943_25553944AC[1]
NG_008932.1:g.15359AC[1]
NM_015627.3:c.112_113delMANE SELECT
NP_056442.2:p.Thr38fs
LRG_276t1:c.112_113del
LRG_276:g.15359AC[1]
NC_000001.10:g.25880434AC[1]
NC_000001.10:g.25880434_25880435del
NM_015627.2:c.112_113delAC

Protein change:

T38fs

Links:

dbSNP: rs763778803

NCBI 1000 Genomes Browser:

rs763778803

Molecular consequence:

NM_015627.3:c.112_113del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hypercholesterolemia, familial, 4 (FHCL4)
Synonyms:: HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 1; HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 2; Hypercholesterolemia, autosomal recessive
Identifiers:: MONDO: MONDO:0011374; MedGen: C1863512; Orphanet: 391665; OMIM: 603813

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001586564	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11326085, 12464675, 28492532
SCV002787149	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 22, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004173389	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001586564

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 14, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002787149

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 22, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004173389

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 11, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.

Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH.

Science. 2001 May 18;292(5520):1394-8. Epub 2001 Apr 26.

PubMed [citation]

PMID:: 11326085

Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.

Eden ER, Patel DD, Sun XM, Burden JJ, Themis M, Edwards M, Lee P, Neuwirth C, Naoumova RP, Soutar AK.

J Clin Invest. 2002 Dec;110(11):1695-702.

PubMed [citation]

PMID:: 12464675
PMCID:: PMC151635

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001586564.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817252). This variant has not been reported in the literature in individuals affected with LDLRAP1-related conditions. This variant is present in population databases (rs763778803, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Thr38Alafs*26) 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002787149.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004173389.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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