Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT

CA10585420

251805 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: d6dfa338-1166-4fde-998b-3f9d599decaa

HGVS expressions

NM_000527.5:c.1359-31_1359-23delinsCGGCT

NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT

NC_000019.10:g.11113504_11113512delinsCGGCT

CM000681.2:g.11113504_11113512delinsCGGCT

NC_000019.9:g.11224180_11224188delinsCGGCT

CM000681.1:g.11224180_11224188delinsCGGCT

NC_000019.8:g.11085180_11085188delinsCGGCT

NG_009060.1:g.29124_29132delinsCGGCT

ENST00000558518.6:c.1359-31_1359-23delinsCGGCT

ENST00000252444.9:n.1613-31_1613-23delinsCGGCT

ENST00000455727.6:c.855-31_855-23delinsCGGCT

ENST00000535915.5:c.1236-31_1236-23delinsCGGCT

ENST00000545707.5:c.978-31_978-23delinsCGGCT

ENST00000557933.5:c.1359-31_1359-23delinsCGGCT

ENST00000558013.5:c.1359-31_1359-23delinsCGGCT

ENST00000558518.5:c.1359-31_1359-23delinsCGGCT

ENST00000559340.1:n.80-31_80-23delinsCGGCT

ENST00000560467.1:n.839-31_839-23delinsCGGCT

NM_000527.4:c.1359-31_1359-23delinsCGGCT

NM_001195798.1:c.1359-31_1359-23delinsCGGCT

NM_001195799.1:c.1236-31_1236-23delinsCGGCT

NM_001195800.1:c.855-31_855-23delinsCGGCT

NM_001195803.1:c.978-31_978-23delinsCGGCT

NR_106946.1:n.31_39delinsCGGCT

NM_001195798.2:c.1359-31_1359-23delinsCGGCT

NM_001195799.2:c.1236-31_1236-23delinsCGGCT

NM_001195800.2:c.855-31_855-23delinsCGGCT

NM_001195803.2:c.978-31_978-23delinsCGGCT

Uncertain Significance

PS3_Supporting PP4 PM2

PS4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_supporting) 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: This variant is absent from gnomAD (gnomAD v2.1.1). - PP4: Variant meets PM2. Identified in 1 FH case from PMID: 8872473 meeting Simon-Broome criteria of possible FH , after alternative causes of high cholesterol were excluded. - PS3: Level 3 assay: PMID 8872473: Heterozygous patient's Epstein-Barr virus transformed lymphoblasts, RNA assays; Heterologous cells (COS), RNA assays: Retention of intron 9 (p.Ser453Argfs*2) ---- functional study is consistent with damaging effect.

PS3_Supporting

Level 3 assay: PMID 8872473: Heterozygous patient's Epstein-Barr virus transformed lymphoblasts, RNA assays; Heterologous cells (COS), RNA assays: Retention of intron 9 (p.Ser453Argfs*2) ---- functional study is consistent with damaging effect.

PP4

Variant meets PM2. Identified in 1 FH case from PMID: 8872473 meeting Simon-Broome criteria of possible FH , after alternative causes of high cholesterol were excluded.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

PS4

only identified in 1 FH case from PMID: 8872473 meeting Simon-Broome criteria of possible FH, so PS4 not MET

Approved on: 2023-03-20

Published on: 2023-03-31

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