NM_000527.5(LDLR):c.1865A>C (p.Asp622Ala) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 23, 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:: RCV000238393.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1865A>C (p.Asp622Ala)]

NM_000527.5(LDLR):c.1865A>C (p.Asp622Ala)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1865A>C (p.Asp622Ala)

HGVS:

NC_000019.10:g.11120111A>C
NG_009060.1:g.35731A>C
NM_000527.5:c.1865A>CMANE SELECT
NM_001195798.2:c.1865A>C
NM_001195799.2:c.1742A>C
NM_001195800.2:c.1361A>C
NM_001195803.2:c.1484A>C
NP_000518.1:p.Asp622Ala
NP_001182727.1:p.Asp622Ala
NP_001182728.1:p.Asp581Ala
NP_001182729.1:p.Asp454Ala
NP_001182732.1:p.Asp495Ala
LRG_274:g.35731A>C
NC_000019.9:g.11230787A>C
c.1865A>C

Protein change:

D454A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001154; dbSNP: rs879255060

NCBI 1000 Genomes Browser:

rs879255060

Molecular consequence:

NM_000527.5:c.1865A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1865A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1742A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1361A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1484A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

Recent activity

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FAM189A1 AND (alive[prop]) (581)
Gene
HLA-DPB1 AND (alive[prop]) (137)
Gene
Transcriptional factor B3 family protein [Arabidopsis thaliana]
Transcriptional factor B3 family protein [Arabidopsis thaliana]
gi|15236028|ref|NP_194891.1|

Protein
WASHC2A AND (alive[prop]) (182)
Gene
PRRC1 proline rich coiled-coil 1 [Homo sapiens]
PRRC1 proline rich coiled-coil 1 [Homo sapiens]
Gene ID:133619

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295726	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003841342	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16159606, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295726

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV003841342

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 23, 2023)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate.

Graham CA, McIlhatton BP, Kirk CW, Beattie ED, Lyttle K, Hart P, Neely RD, Young IS, Nicholls DP.

Atherosclerosis. 2005 Oct;182(2):331-40.

PubMed [citation]

PMID:: 16159606

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295726.2

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

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

From 3billion, SCV003841342.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR related disorder (ClinVar ID: VCV000252093 / PMID: 16159606). However, the evidence of pathogenicity is insufficient at this time. A different missense change at the same codon (p.Asp622Asn) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252092). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Aug 5, 2023

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