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NM_000527.5(LDLR):c.2T>C (p.Met1Thr) AND Hypercholesterolemia, familial, 1

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Apr 22, 2022
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV000509477.5

Allele description [Variation Report for NM_000527.5(LDLR):c.2T>C (p.Met1Thr)]

NM_000527.5(LDLR):c.2T>C (p.Met1Thr)

Genes:
LDLR-AS1:LDLR antisense RNA 1 [Gene - HGNC]
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.2T>C (p.Met1Thr)
Other names:
NM_000527.5(LDLR):c.2T>C; p.Met1Thr
HGVS:
  • NC_000019.10:g.11089550T>C
  • NG_009060.1:g.5170T>C
  • NM_000527.5:c.2T>CMANE SELECT
  • NM_001195798.2:c.2T>C
  • NM_001195799.2:c.2T>C
  • NM_001195800.2:c.2T>C
  • NM_001195803.2:c.2T>C
  • NP_000518.1:p.Met1Thr
  • NP_000518.1:p.Met1Thr
  • NP_001182727.1:p.Met1Thr
  • NP_001182728.1:p.Met1Thr
  • NP_001182729.1:p.Met1Thr
  • NP_001182732.1:p.Met1Thr
  • LRG_274t1:c.2T>C
  • LRG_274:g.5170T>C
  • LRG_274p1:p.Met1Thr
  • NC_000019.9:g.11200226T>C
  • NM_000527.4:c.2T>C
  • NR_163945.1:n.110A>G
Protein change:
M1T
Links:
dbSNP: rs1555800701
NCBI 1000 Genomes Browser:
rs1555800701
Molecular consequence:
  • NM_000527.5:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195798.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195799.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195800.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195803.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_000527.5:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_163945.1:n.110A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hypercholesterolemia, familial, 1
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000607400Fundacion Hipercolesterolemia Familiar - SAFEHEART
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 1, 2016) 		germlineresearch

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

SCV002506385ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)		Likely pathogenic
(Apr 22, 2022) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch, curation

Citations

PubMed

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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607400.2

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506385.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000527.5(LDLR):c.2T>C (p.Met1Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012) The supporting evidence is as follows: PM2 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. 4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines.

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

Last Updated: Jun 23, 2024