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]

Variant: NM_000527.5(LDLR):c.770_771delinsAC (p.Arg257His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023759

183094 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7b14115d-b9ac-4596-8f7e-516261d36d62

Approved on: 2022-08-26

Published on: 2022-12-24

HGVS expressions

NM_000527.5:c.770_771delinsAC

NM_000527.5(LDLR):c.770_771delinsAC (p.Arg257His)

NC_000019.10:g.11106640_11106641delinsAC

CM000681.2:g.11106640_11106641delinsAC

NC_000019.9:g.11217316_11217317delinsAC

CM000681.1:g.11217316_11217317delinsAC

NC_000019.8:g.11078316_11078317delinsAC

NG_009060.1:g.22260_22261delinsAC

ENST00000558518.6:c.770_771delinsAC

ENST00000252444.9:n.1024_1025delinsAC

ENST00000455727.6:c.314-752_314-751delinsAC

ENST00000535915.5:c.647_648delinsAC

ENST00000545707.5:c.389_390delinsAC

ENST00000557933.5:c.770_771delinsAC

ENST00000558013.5:c.770_771delinsAC

ENST00000558518.5:c.770_771delinsAC

ENST00000558528.1:n.285_286delinsAC

ENST00000560467.1:n.370_371delinsAC

NM_000527.4:c.770_771delinsAC

NM_001195798.1:c.770_771delinsAC

NM_001195799.1:c.647_648delinsAC

NM_001195800.1:c.314-752_314-751delinsAC

NM_001195803.1:c.389_390delinsAC

NM_001195798.2:c.770_771delinsAC

NM_001195799.2:c.647_648delinsAC

NM_001195800.2:c.314-752_314-751delinsAC

NM_001195803.2:c.389_390delinsAC

Uncertain Significance

PM2

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

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.770_771delinsAC (p.Arg257His) 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 is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met

PVS1

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

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met

BS4

no available case data

BS3

there is no functional study performed for this variant

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met

BS2

no available case data

BP5

not applicable

BP7

variant is missense, so not met

BP4

No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create GT C) there are no GT nearby, but variant is essentially missense, so BP4 cannot be met until altered amino acid can be evaluated

BP1

not applicable

BP2

no available case data

BP3

not applicable

PS2

no available case data

PS4

no available case data

PS3

there is no functional study performed for this variant

PS1

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

PP3

No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create GT C) there are no GT nearby, so PP3 is not met

PP2

not applicable

PP4

no available case data

PP1

no available case data

PM6

no available case data

PM3

no available case data

PM1

variant is missense and meets PM2, but it is not in exon 4 and does not alter 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.770G>A (p.Arg257Gln) (ClinVar ID: 927149) - classified as VUS by these guidelines NM_000527.5(LDLR):c.770G>C (p.Arg257Pro) (ClinVar ID: 440602) - 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

Curation History

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