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NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del) AND Homozygous familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 11, 2019
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:
RCV004017502.1

Allele description [Variation Report for NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del)]

NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del)

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del)
Other names:
G197del; FH Lithuania; FH Piscataway; NM_000527.5(LDLR):c.651TGG[1]
HGVS:
  • NC_000019.10:g.11105557TGG[1]
  • NG_009060.1:g.21177TGG[1]
  • NG_009060.1:g.21180_21182del
  • NM_000527.5:c.651TGG[1]MANE SELECT
  • NM_001195798.2:c.651TGG[1]
  • NM_001195799.2:c.528TGG[1]
  • NM_001195800.2:c.314-1832_314-1830del
  • NM_001195803.2:c.314-1005_314-1003del
  • NP_000518.1:p.Gly219del
  • NP_001182727.1:p.Gly219del
  • NP_001182728.1:p.Gly178del
  • LRG_274t1:c.652_654del
  • LRG_274:g.21177TGG[1]
  • NC_000019.10:g.11105560_11105562delTGG
  • NC_000019.9:g.11216233TGG[1]
  • NC_000019.9:g.11216233_11216235del
  • NG_009060.1:g.21180_21182del
  • NM_000527.4:c.652_654delGGT
  • NM_000527.4:c.654_656delTGG
  • NM_000527.5:c.654_656delMANE SELECT
  • c.654_656del
Protein change:
G178del; GLY197DEL
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000094; OMIM: 606945.0005; dbSNP: rs121908027
NCBI 1000 Genomes Browser:
rs121908027
Molecular consequence:
  • NM_000527.5:c.651TGG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001195798.2:c.651TGG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001195799.2:c.528TGG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001195800.2:c.314-1832_314-1830del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1005_314-1003del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Homozygous familial hypercholesterolemia
Synonyms:
Familial hypercholesterolemia - homozygous
Identifiers:
MONDO: MONDO:0018328; MedGen: C0342881

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004847786Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 11, 2019) 		germlineclinical testing

PubMed (15)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Recent origin and spread of a common Lithuanian mutation, G197del LDLR, causing familial hypercholesterolemia: positive selection is not always necessary to account for disease incidence among Ashkenazi Jews.

Durst R, Colombo R, Shpitzen S, Avi LB, Friedlander Y, Wexler R, Raal FJ, Marais DA, Defesche JC, Mandelshtam MY, Kotze MJ, Leitersdorf E, Meiner V.

Am J Hum Genet. 2001 May;68(5):1172-88. Epub 2001 Apr 17.

PubMed [citation]
PMID:
11309683
PMCID:
PMC1226098

LDL-R and Apo-B-100 gene mutations in Polish familial hypercholesterolemias.

Górski B, Kubalska J, Naruszewicz M, Lubiński J.

Hum Genet. 1998 May;102(5):562-5.

PubMed [citation]
PMID:
9654205
See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847786.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (15)

Description

The p.Gly219del variant in LDLR (also known as FH Lithuania and G197del) has been reported in >75 families with hypercholesterolemia (Hobbs 1990, Meiner 1991, Gudnason 1993, Gorski 1998, Mandelshtam 1998, Heath 1999, Durst 2001, Kuhrova 2002, Taylor 2007, Junyent 2008, Chmara 2010, Tichy 2012, Hooper 2012, Sharifi 2016, Durst 2017, Smyth 2018). It is considered to be a founder mutation in the Ashkenazi Jewish population (Meiner 1991, Durst 2001). This variant has also been identified in 0.05% (5/10062) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 226329). This variant is a deletion of 1 amino acid at position 219 and is not predicted to alter the protein reading-frame. In vitro functional studies support an impact on protein function (Hobbs 1990). This variant meets the following ACMG/AMP Criteria: PS4, PM2, PM4_Supporting, PS3_Supporting. Based on these criteria, the variant would be classified as likely pathogenic but its recognized role as a founder mutation lends additional weight. In summary, the p.Gly219del is classified as pathogenic for autosomal dominant hypercholesterolemia.

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

Last Updated: Oct 13, 2024