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NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr) AND Familial hypercholesterolemia

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Apr 1, 2024
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:
RCV001186038.10

Allele description [Variation Report for NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr)]

NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr)

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.352G>T (p.Asp118Tyr)
Other names:
FH Naples-3
HGVS:
  • NC_000019.10:g.11105258G>T
  • NG_009060.1:g.20878G>T
  • NM_000527.5:c.352G>TMANE SELECT
  • NM_001195798.2:c.352G>T
  • NM_001195799.2:c.229G>T
  • NM_001195800.2:c.314-2134G>T
  • NM_001195803.2:c.314-1307G>T
  • NP_000518.1:p.Asp118Tyr
  • NP_000518.1:p.Asp118Tyr
  • NP_001182727.1:p.Asp118Tyr
  • NP_001182728.1:p.Asp77Tyr
  • LRG_274t1:c.352G>T
  • LRG_274:g.20878G>T
  • LRG_274p1:p.Asp118Tyr
  • NC_000019.9:g.11215934G>T
  • NM_000527.4:c.352G>T
  • c.352G>T
  • p.(Asp118Tyr)
Protein change:
D118Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001708; dbSNP: rs730882080
NCBI 1000 Genomes Browser:
rs730882080
Molecular consequence:
  • NM_001195800.2:c.314-2134G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1307G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.352G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.352G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.229G>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
unknown functional consequence - Comment(s)

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001352368Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Dec 5, 2023) 		germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV001411750Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 5, 2024) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV005075905Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Apr 1, 2024) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group.

Gazzotti M, Casula M, Bertolini S, Capra ME, Olmastroni E, Catapano AL, Pederiva C; LIPIGEN Paediatric Group..

Front Genet. 2022;13:912510. doi: 10.3389/fgene.2022.912510. Erratum in: Front Genet. 2023 Apr 18;14:1113454. doi: 10.3389/fgene.2023.1113454.

PubMed [citation]
PMID:
35795214
PMCID:
PMC9251337

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
See all PubMed Citations (14)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001352368.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This missense variant replaces aspartic acid with tyrosine at codon 118 of the LDLR protein. This variant is also known as p.Asp97Tyr in the mature protein, and FH Naples 3 in the literature. This variant alters a conserved AA1 residue in the LDLR type A repeat 3 of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study has shown that this variant results in 30% of normal LDLR activity when in compound heterozygous state with a different pathogenic LDLR missense variant (PMID: 9974426). This variant has shown an unclear functional consequence in a high throughput screening assay in HeLa cells (PMID: 25647241). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9974426, 28161202, 28965616, 28958694, 31947532, 35795214; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in at least two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 23375686, 31947532, 36325061). This variant has been identified in 3/250932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001411750.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 118 of the LDLR protein (p.Asp118Tyr). This variant is present in population databases (rs730882080, gnomAD 0.003%). This missense change has been observed in individuals with LDLR-related conditions (PMID: 9974426, 11317362, 23375686, 25487149, 28161202, 28965616, 31345425). This variant is also known as D97Y, FH-Napoli-3 or Naples-3. ClinVar contains an entry for this variant (Variation ID: 183085). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005075905.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: LDLR c.352G>T (p.Asp118Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250932 control chromosomes. c.352G>T has been reported in the literature in multiple heterozygous individuals affected with Familial Hypercholesterolemia, as well as multiple compound heterozygous individuals affected with Homozygous Familial Hypercholesterolemia (e.g., Bertolini_1999, Scicali_2018, Di Taranto_2020, Du_2022). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect. One study demonstrates that LDLR activity in an individual with the variant is approximately 30%, however this individual also carried the pathogenic variant p.V523M (Betolini_1999). Another study investigating whether this variant is disruptive demonstrated unclear results (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 31947532, 36325061, 28958694, 25647241). ClinVar contains an entry for this variant (Variation ID: 183085). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024