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.2106G>C (p.Met702Ile)

CA038621

2057364 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: acb3dcf0-547f-4366-8fd2-868b9ff4d944

Approved on: 2024-08-30

Published on: 2024-10-03

HGVS expressions

NM_000527.5:c.2106G>C

NM_000527.5(LDLR):c.2106G>C (p.Met702Ile)

NC_000019.10:g.11120488G>C

CM000681.2:g.11120488G>C

NC_000019.9:g.11231164G>C

CM000681.1:g.11231164G>C

NC_000019.8:g.11092164G>C

NG_009060.1:g.36108G>C

ENST00000252444.10:c.2364G>C

ENST00000559340.2:c.*175G>C

ENST00000560467.2:c.1986G>C

ENST00000558518.6:c.2106G>C

ENST00000252444.9:c.2360G>C

ENST00000455727.6:c.1602G>C

ENST00000535915.5:c.1983G>C

ENST00000545707.5:c.1606+255G>C

ENST00000557933.5:c.2106G>C

ENST00000558013.5:c.2106G>C

ENST00000558518.5:c.2106G>C

NM_000527.4:c.2106G>C

NM_001195798.1:c.2106G>C

NM_001195799.1:c.1983G>C

NM_001195800.1:c.1602G>C

NM_001195803.1:c.1606+255G>C

NM_001195798.2:c.2106G>C

NM_001195799.2:c.1983G>C

NM_001195800.2:c.1602G>C

NM_001195803.2:c.1606+255G>C

Uncertain Significance

PM2

BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 BA1 PM6 PVS1 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.2106G>C (p.Met702Ile) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on August 30, 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003294 (0.0033%) in South Asian exomes (gnomAD v4.1.0). It is below 0.02%, so PM2 is met.

PM2

PopMax MAF = 0.00003294 (0.0033%) in South Asian exomes (gnomAD v4.1.0). It is below 0.02%, so PM2 is met.

BS4

no case data

BS3

no published functional studies

BS1

FAF = 0.000008750 (0.000875%) in South Asian exomes+genomes (gnomAD v4.1.0). It is not above 0.2%, so BS1 is not met

BS2

no case data

BP5

not applicable

BP7

missense, not applicable

BP2

no case data

BP3

not applicable

BP4

REVEL = 0.501. It is not below 0.50, so not met

BP1

not applicable

BA1

FAF = 0.000008750 (0.000875%) in South Asian exomes+genomes (gnomAD v4.1.0). It is not above 0.5%, so BA1 is not met

PM6

no case data

PVS1

missense and not in exon 1, not applicable

PM3

no case data

PM1

variant is missense and meets PM2, but is not in exon 4 and does not alter Cys, so not met

PM4

missense, not applicable

PM5

No additional missense variants at the same codon leading to a different amino acid change have been reported

PS2

no case data

PS4

no case data

PS3

no published functional studies

PS1

There is one other variant in same codon: NM_000527.5(LDLR):c.2106G>A (p.Met702Ile), which is classified as Uncertain significance by these guidelines

PP4

no case data

PP1

no case data

PP3

REVEL = 0.501, which is below 0.75, so PP3 is not met

PP2

not applicable

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