NM_000527.5(LDLR):c.1845G>A (p.Glu615=) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Aug 29, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000237596.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1845G>A (p.Glu615=)]

NM_000527.5(LDLR):c.1845G>A (p.Glu615=)

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.1845G>A (p.Glu615=)

Other names:

NM_000527.5(LDLR):c.1845G>A; p.Glu615=

HGVS:

NC_000019.10:g.11116998G>A
NG_009060.1:g.32618G>A
NM_000527.5:c.1845G>AMANE SELECT
NM_001195798.2:c.1845G>A
NM_001195799.2:c.1722G>A
NM_001195800.2:c.1341G>A
NM_001195803.2:c.1464G>A
NP_000518.1:p.Glu615=
NP_000518.1:p.Glu615=
NP_001182727.1:p.Glu615=
NP_001182728.1:p.Glu574=
NP_001182729.1:p.Glu447=
NP_001182732.1:p.Glu488=
LRG_274t1:c.1845G>A
LRG_274:g.32618G>A
LRG_274p1:p.Glu615=
NC_000019.9:g.11227674G>A
NM_000527.4:c.1845G>A
c.1845G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000612; dbSNP: rs879255047

NCBI 1000 Genomes Browser:

rs879255047

Molecular consequence:

NM_000527.5:c.1845G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.1845G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.1722G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195800.2:c.1341G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195803.2:c.1464G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295696	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,
SCV000503422	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000748155	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002817134	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Aug 29, 2022)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	germline	yes	2	not provided	not provided	2601	not provided	clinical testing, literature only

Citations

PubMed

Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia.

Taylor A, Tabrah S, Wang D, Sozen M, Duxbury N, Whittall R, Humphries SE, Norbury G.

Clin Genet. 2007 Jun;71(6):561-8.

PubMed [citation]

PMID:: 17539906

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, SCV000295696.2

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503422.1

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

Description

subject mutated among 2600 FH index cases screened = 1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		1	not provided	not provided	not provided

From Iberoamerican FH Network, SCV000748155.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002817134.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000527.5(LDLR):c.1845G>A (p.Glu615=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: The only >10,000 subpopulation is European (Non-Finnish), in which the variant is absent. So PM2 is met. PP3: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = -1.8; canonical donor wt = 4.48. Ratio: -1.8/4.48 = -0.4 ---- It is below 0.8. Variant is predicted to alter splicing. So PP3 is met. PP4: Variant meets PM2 and is identified in 1 case fulfilling Simon-Broome criteria for possible FH published in PMID: 17539906 (Taylor et al., 2007). So PP4 is met.

#	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

Last Updated: Sep 29, 2024

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