NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr) AND Hypercholesterolemia, familial, 4

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: May 24, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000005042.19

Allele description [Variation Report for NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr)]

NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.11

Genomic location:

Preferred name:

NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr)

Other names:

P202H

HGVS:

NC_000001.11:g.25563142C>A
NG_008932.1:g.24558C>A
NM_015627.3:c.605C>AMANE SELECT
NP_056442.2:p.Ser202Tyr
NP_056442.2:p.Ser202Tyr
LRG_276t1:c.605C>A
LRG_276:g.24558C>A
LRG_276p1:p.Ser202Tyr
NC_000001.10:g.25889633C>A
NM_015627.2:c.605C>A
p.(Ser202Tyr)

Protein change:

S202Y; PRO202HIS

Links:

OMIM: 605747.0004; dbSNP: rs121908326

NCBI 1000 Genomes Browser:

rs121908326

Molecular consequence:

NM_015627.3:c.605C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025218	OMIM	no assertion criteria provided	Pathogenic (May 18, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000987666	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001031361	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Dec 31, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001259183	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Jul 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11326085, 25911074 Citation Link,
SCV001653675	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28353356, 28965616, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000025218.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a Lebanese family (ARH4) with autosomal recessive hypercholesterolemia (FHCL4; 603813), Garcia et al. (2001) found that all affected individuals were homozygous for a C-to-A transversion at nucleotide 605 of the ARH gene, resulting in a pro-to-his substitution at codon 202 (P202H). Family members had plasma total cholesterol of 520 to 610 mg/dl, with LDL cholesterol ranging from 392 to 520 dl.

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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987666.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001031361.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001259183.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

#	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 Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653675.1

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

Description

Identified at heterozygous status in a patient with clinical suspect of Familial Hypercholesterolemia without pathogenic variants in LDLR, APOB, PCSK9, APOE, STAP1, ABCG5, ABCG8, LIPA and other lipid-related genes by next-generation sequencing. Likely pathogenic if in trans with an additional LDLRAP1 variant; probably affecting cholesterol levels at heterozygous status.

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

Last Updated: Nov 24, 2024

ClinVar

Relating variation to medicine