NM_000527.5(LDLR):c.1836C>T (p.Ala612=) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 21, 2023
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:: RCV000456101.11

Allele description [Variation Report for NM_000527.5(LDLR):c.1836C>T (p.Ala612=)]

NM_000527.5(LDLR):c.1836C>T (p.Ala612=)

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.1836C>T (p.Ala612=)

Other names:

NM_000527.5(LDLR):c.1836C>T; p.Ala612=

HGVS:

NC_000019.10:g.11116989C>T
NG_009060.1:g.32609C>T
NM_000527.5:c.1836C>TMANE SELECT
NM_001195798.2:c.1836C>T
NM_001195799.2:c.1713C>T
NM_001195800.2:c.1332C>T
NM_001195803.2:c.1455C>T
NP_000518.1:p.Ala612=
NP_000518.1:p.Ala612=
NP_001182727.1:p.Ala612=
NP_001182728.1:p.Ala571=
NP_001182729.1:p.Ala444=
NP_001182732.1:p.Ala485=
LRG_274t1:c.1836C>T
LRG_274:g.32609C>T
LRG_274p1:p.Ala612=
NC_000019.9:g.11227665C>T
NM_000527.4:c.1836C>T
c.1836C>T
p.Ala612Ala

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000249; dbSNP: rs143872778

NCBI 1000 Genomes Browser:

rs143872778

Molecular consequence:

NM_000527.5:c.1836C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.1836C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.1713C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195800.2:c.1332C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195803.2:c.1455C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Danio rerio core binding factor B subunit (CBFB) mRNA, complete cds
Danio rerio core binding factor B subunit (CBFB) mRNA, complete cds
gi|12247460|gb|AF278758.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000539509	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 24, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000697212	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17347910, 20145306, 22881376, 28145427, 29870584 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000539509

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 24, 2017)

germline

clinical testing

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

SCV000697212

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 21, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

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	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations.

Widhalm K, Dirisamer A, Lindemayr A, Kostner G.

J Inherit Metab Dis. 2007 Apr;30(2):239-47. Epub 2007 Mar 8.

PubMed [citation]

PMID:: 17347910

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000539509.1

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

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is a silent variant in LDLR. It is classified as DM in HGMD. This variant has been reported in 7 patients with familial hypercholesterolemia in one study (Widhalm 2007). This variant is classified in ClinVar with 1 star as VUS by Mayo Clinic and as Likely Benign by British Heart Foundation. The variant has a Max MAF of 0.03% in ExAC (23 alleles) and 0.03% in gnomAD (43 alleles).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697212.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: LDLR c.1836C>T alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 251468 control chromosomes (i.e., 46 heterozygotes; gnomAD v2.1 Exomes dataset). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease (0.00018 vs 0.001), allowing no conclusion about variant significance. The variant, c.1836C>T, has been reported in the literature in individuals affected with premature atherosclerosis and/or hypercholesterolaemia (e.g., Widhalm_2007, Chmara_2010, Saracoglu_2018). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 28145427, 22881376, 17347910, 29870584). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (benign, n = 1; likely benign, n = 5; VUS, n = 4; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as likely 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

Last Updated: Oct 20, 2024

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