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 (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
SCV001346424	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32009526, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001346424

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 6, 2023)

germline

clinical testing

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

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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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

ClinVar

Relating variation to medicine