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NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala) AND Familial hypercholesterolemia

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 6, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001181308.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala)]

NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala)

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.1942T>G (p.Ser648Ala)
Other names:
NM_000527.5(LDLR):c.1942T>G; p.Ser648Ala
HGVS:
  • NC_000019.10:g.11120188T>G
  • NG_009060.1:g.35808T>G
  • NM_000527.5:c.1942T>GMANE SELECT
  • NM_001195798.2:c.1942T>G
  • NM_001195799.2:c.1819T>G
  • NM_001195800.2:c.1438T>G
  • NM_001195803.2:c.1561T>G
  • NP_000518.1:p.Ser648Ala
  • NP_000518.1:p.Ser648Ala
  • NP_001182727.1:p.Ser648Ala
  • NP_001182728.1:p.Ser607Ala
  • NP_001182729.1:p.Ser480Ala
  • NP_001182732.1:p.Ser521Ala
  • LRG_274t1:c.1942T>G
  • LRG_274:g.35808T>G
  • LRG_274p1:p.Ser648Ala
  • NC_000019.9:g.11230864T>G
  • NC_000019.9:g.11230864T>G
  • NM_000527.4:c.1942T>G
Protein change:
S480A
Links:
Molecular consequence:
  • NM_000527.5:c.1942T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1942T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1819T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1438T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1561T>G - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001346424Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Oct 6, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants.

Pottinger TD, Puckelwartz MJ, Pesce LL, Robinson A, Kearns S, Pacheco JA, Rasmussen-Torvik LJ, Smith ME, Chisholm R, McNally EM.

J Am Heart Assoc. 2020 Feb 4;9(3):e013808. doi: 10.1161/JAHA.119.013808. Epub 2020 Feb 3.

PubMed [citation]
PMID:
32009526
PMCID:
PMC7033893

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, SCV001346424.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This missense variant replaces serine with alanine at codon 648 in the LDLR type B repeat 6 EGF precursor homology domain of the LDLR protein. This variant is also known as p.Ser627Ala in the mature protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with maximum total cholesterol level of 251 mg/dL (PMID: 32009526). This variant has been identified in 4/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ser648Pro, is reported to cause disease (ClinVar variation ID: 252120), indicating that serine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 1, 2024