NM_000527.5(LDLR):c.226G>T (p.Gly76Trp) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 22, 2020
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:: RCV001182218.7

Allele description [Variation Report for NM_000527.5(LDLR):c.226G>T (p.Gly76Trp)]

NM_000527.5(LDLR):c.226G>T (p.Gly76Trp)

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.226G>T (p.Gly76Trp)

Other names:

NM_000527.5(LDLR):c.226G>T

HGVS:

NC_000019.10:g.11102699G>T
NG_009060.1:g.18319G>T
NM_000527.5:c.226G>TMANE SELECT
NM_001195798.2:c.226G>T
NM_001195799.2:c.190+2354G>T
NM_001195800.2:c.226G>T
NM_001195803.2:c.226G>T
NP_000518.1:p.Gly76Trp
NP_000518.1:p.Gly76Trp
NP_001182727.1:p.Gly76Trp
NP_001182729.1:p.Gly76Trp
NP_001182732.1:p.Gly76Trp
LRG_274t1:c.226G>T
LRG_274:g.18319G>T
NC_000019.9:g.11213375G>T
NM_000527.4(LDLR):c.226G>T
NM_000527.4:c.226G>T
c.226G>T

Protein change:

G76W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000035; dbSNP: rs574337291

NCBI 1000 Genomes Browser:

rs574337291

Molecular consequence:

NM_001195799.2:c.190+2354G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001347577	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (May 15, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423041	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 25741862, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001347577

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(May 15, 2017)

germline

clinical testing

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

SCV001423041

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 22, 2020)

germline

curation

PubMed (2)
[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, curation

Citations

PubMed

The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia.

Benito-Vicente A, Alves AC, Etxebarria A, Medeiros AM, Martin C, Bourbon M.

Genet Med. 2015 Dec;17(12):980-8. doi: 10.1038/gim.2015.14. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741862

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 Color Diagnostics, LLC DBA Color Health, SCV001347577.1

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423041.2

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

Description

The p.Gly76Trp variant in LDLR has been reported in at least 1 Portuguese individual with familial hypercholesterolemia (PMID: 17765246), and was absent from large population studies. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: rs574337291). In vitro functional studies provide some evidence that the p.Gly76Trp variant may not impact protein function (PMID: 25741862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly76Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, BS3_supporting (Richards 2015).

#	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: May 7, 2024

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