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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
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001347577Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely benign
(May 15, 2017) 		germlineclinical testing

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

SCV001423041Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 22, 2020) 		germlinecuration

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024