NM_000527.5(LDLR):c.1304_1307delinsTGGC (p.Glu435_Val436delinsValAla) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 17, 2017
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:: RCV002380907.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1304_1307delinsTGGC (p.Glu435_Val436delinsValAla)]

NM_000527.5(LDLR):c.1304_1307delinsTGGC (p.Glu435_Val436delinsValAla)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1304_1307delinsTGGC (p.Glu435_Val436delinsValAla)

HGVS:

NC_000019.10:g.11113395_11113398delinsTGGC
NG_009060.1:g.29015_29018delinsTGGC
NM_000527.5:c.1304_1307delinsTGGCMANE SELECT
NM_001195798.2:c.1304_1307delinsTGGC
NM_001195799.2:c.1181_1184delinsTGGC
NM_001195800.2:c.800_803delinsTGGC
NM_001195803.2:c.923_926delinsTGGC
NP_000518.1:p.Glu435_Val436delinsValAla
NP_000518.1:p.Glu435_Val436delinsValAla
NP_001182727.1:p.Glu435_Val436delinsValAla
NP_001182728.1:p.Glu394_Val395delinsValAla
NP_001182729.1:p.Glu267_Val268delinsValAla
NP_001182732.1:p.Glu308_Val309delinsValAla
LRG_274t1:c.1304_1307delAGGTinsTGGC
LRG_274:g.29015_29018delinsTGGC
LRG_274p1:p.Glu435_Val436delinsValAla
NC_000019.9:g.11224071_11224074delinsTGGC
NM_000527.4:c.1304_1307delAGGTinsTGGC

Molecular consequence:

NM_000527.5:c.1304_1307delinsTGGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1304_1307delinsTGGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1181_1184delinsTGGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.800_803delinsTGGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.923_926delinsTGGC - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002689870	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 17, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21382890, 26608663, 9184256 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002689870

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 17, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.

van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJ, Wiegman A.

Circulation. 2011 Mar 22;123(11):1167-73. doi: 10.1161/CIRCULATIONAHA.110.979450. Epub 2011 Mar 7.

PubMed [citation]

PMID:: 21382890

The distribution and characteristics of LDL receptor mutations in China: A systematic review.

Jiang L, Sun LY, Dai YF, Yang SW, Zhang F, Wang LY.

Sci Rep. 2015 Nov 26;5:17272. doi: 10.1038/srep17272. Review.

PubMed [citation]

PMID:: 26608663
PMCID:: PMC4660303

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002689870.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.1304_1307delAGGTinsTGGC variant (also known as p.E435_V436delinsVA), located in coding exon 9 of the LDLR gene, results from an in-frame deletion of AGGT and insertion of TGGC at nuclelotide positions 1304 to 1307. This results in the deletion of glutamic acid and valine residues and the insertion of valine and alanine residues at codons 435 and 436, respectively. Missense alterations at both of these codons have been reported in association with familial hypercholesterolemia (FH); additionally, one (p.V436A, c.1307T>C) has been shown to co-segregate with disease and reported to result in deficient LDL-receptor expression (Lombardi P et al. Clin. Genet., 1997 Apr;51:286-7; Selberg O et al. J Appl Res., 2003;3:495-504; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Jiang L et al. Sci Rep, 2015 Nov;5:17272). These amino acid positions are not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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 1, 2024

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