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.1976C>A (p.Thr659Asn)

CA10585704

252141 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 9949e5e8-d117-4913-a756-ec01893ced1c

HGVS expressions

NM_000527.5:c.1976C>A

NM_000527.5(LDLR):c.1976C>A (p.Thr659Asn)

NC_000019.10:g.11120222C>A

CM000681.2:g.11120222C>A

NC_000019.9:g.11230898C>A

CM000681.1:g.11230898C>A

NC_000019.8:g.11091898C>A

NG_009060.1:g.35842C>A

ENST00000558518.6:c.1976C>A

ENST00000252444.9:n.2230C>A

ENST00000455727.6:c.1472C>A

ENST00000535915.5:c.1853C>A

ENST00000545707.5:c.1595C>A

ENST00000557933.5:c.1976C>A

ENST00000558013.5:c.1976C>A

ENST00000558518.5:c.1976C>A

ENST00000559340.1:n.557C>A

NM_000527.4:c.1976C>A

NM_001195798.1:c.1976C>A

NM_001195799.1:c.1853C>A

NM_001195800.1:c.1472C>A

NM_001195803.1:c.1595C>A

NM_001195798.2:c.1976C>A

NM_001195799.2:c.1853C>A

NM_001195800.2:c.1472C>A

NM_001195803.2:c.1595C>A

Uncertain Significance

PM2 BS3

PM3 PM1 PM4 PM5 PM6 PVS1 BS2 BS4 BS1 BP7 BP2 BP4 PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3

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.1976C>A (p.Thr659Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BS3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00002413 (0.002413%) in African/African American genomes (gnomAD v3.1.2). BS3 - Level 1 assays: PMID 32015373: Heterologous cells, FACS assays - result - 96% cell surface LDLR, 99% LDL-LDLR binding and 97% uptake. ---- functional study is consistent with no damaging effect.

PM2

PopMax MAF = 0.00002413 (0.002413%) in African/African American genomes (gnomAD v3.1.2), so PM2 is Met.

BS3

Level 1 assays: PMID 32015373: Heterologous cells, FACS assays - result - 96% cell surface LDLR, 99% LDL-LDLR binding and 97% uptake. ---- functional study is consistent with no damaging effect, so BS3 is Met.

PM3

Not observed in trans with other LP/P variants, so PM3 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1975A>C (p.Thr659Pro)(ClinVar ID: 252140) - Uncertain significance - insufficient evidence by these guidelines There are no more variants in the same codon classified as Pathogenic by these guidelines.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

PVS1

Variant is missense, so PVS1 is Not Met.

BS2

Case-control data not reported, so BS2 is Not Met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS1

No FAF, just total MAF = 0.000006571 (0.0006571%) genomes (gnomAD v3.1.2), so BA1 is not met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Not observed in trans with other LP/P variants, so BP2 is Not Met.

BP4

REVEL = 0.707. It is not below 0.50, so BP4 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS4

Variant meets PM2, but case data not reported, so PS4 is Not Met.

PS3

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

BA1

No FAF, just total MAF = 0.000006571 (0.0006571%) genomes (gnomAD v3.1.2), so BA1 is not met.

PP4

Variant meets PM2 but phenotype data is not reported, so PP4 is Not Met.

PP1

Segregation data not reported, so PP1 is Not Met.

PP3

REVEL = 0.707. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) there is no a GT nearby. --- PP3 is not met.

Approved on: 2023-03-20

Published on: 2023-03-31

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