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]

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Variant: NM_000527.5(LDLR):c.770G>C (p.Arg257Pro)

CA404079930

440602 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 904d2a2f-31e6-4db5-904e-e74c4a7cfd07

Approved on: 2022-08-29

Published on: 2022-12-24

HGVS expressions

NM_000527.5:c.770G>C

NM_000527.5(LDLR):c.770G>C (p.Arg257Pro)

NC_000019.10:g.11106640G>C

CM000681.2:g.11106640G>C

NC_000019.9:g.11217316G>C

CM000681.1:g.11217316G>C

NC_000019.8:g.11078316G>C

NG_009060.1:g.22260G>C

ENST00000558518.6:c.770G>C

ENST00000252444.9:n.1024G>C

ENST00000455727.6:c.314-752G>C

ENST00000535915.5:c.647G>C

ENST00000545707.5:c.389G>C

ENST00000557933.5:c.770G>C

ENST00000558013.5:c.770G>C

ENST00000558518.5:c.770G>C

ENST00000558528.1:n.285G>C

ENST00000560467.1:n.370G>C

NM_000527.4:c.770G>C

NM_001195798.1:c.770G>C

NM_001195799.1:c.647G>C

NM_001195800.1:c.314-752G>C

NM_001195803.1:c.389G>C

NM_001195798.2:c.770G>C

NM_001195799.2:c.647G>C

NM_001195800.2:c.314-752G>C

NM_001195803.2:c.389G>C

Uncertain Significance

PM2

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

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.770G>C (p.Arg257Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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 was not identified in gnomAD (gnomAD v2.1.1).

PM2

This variant was not identified in gnomAD (gnomAD v2.1.1)

PM6

there are no reports of this variant being identified de novo, so not met

PM3

there are no reports of this variant being identified in index cases with other variants, so not met

PM1

variant is missense and meets PM2, but it is not in exon 4 nor does it change Cys, so not met

PM4

variant is missense, so not met

PM5

There are 4 other missense variants in the same codon: NM_000527.5(LDLR):c.769C>T (p.Arg257Trp) (ClinVar ID: 251446) - classified as VUS by these guidelines NM_000527.5(LDLR):c.770_771delinsAC (p.Arg257His) (ClinVar ID: 183094) - classified as VUS by these guidelines NM_000527.5(LDLR):c.770G>A (p.Arg257Gln) (ClinVar ID: 927149) - classified as VUS by these guidelines NM_000527.5(LDLR):c.770G>T (p.Arg257Leu) (ClinVar ID: 251447) - classified as VUS by these guidelines so PM5 is not met

BS2

there are no reports of this variant being identified in normolipidemic individuals, so not met

BS4

there are no segregation data, so not met

BS3

there are no functional studies for this variant

BS1

This variant was not identified in gnomAD (gnomAD v2.1.1)

BP2

there are no reports of this variant being identified in index cases with other variants, so not met

BP3

not applicable

BP5

not applicable

BP7

variant is missense, so not met

PS2

there are no reports of this variant being identified de novo, so not met

PS4

there are no reports of this variant being identified in index cases who fulfill clinical FH criteria, so not met

PS3

there are no functional studies for this variant

PS1

There are no other variants that lead to the same amino acid change, so not met

BA1

This variant was not identified in gnomAD (gnomAD v2.1.1)

PVS1

variant is missense and not in initiation codon, so not met

PP1

there are no segregation data, so not met

PP4

there are no reports of this variant being identified in index cases who fulfill clinical FH criteria, so not met

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