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>A (p.Arg257Gln)

CA029330

927149 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 5b9948ec-51fe-4292-885d-a0cb29a9bdd2

Approved on: 2022-08-29

Published on: 2022-12-24

HGVS expressions

NM_000527.5:c.770G>A

NM_000527.5(LDLR):c.770G>A (p.Arg257Gln)

NC_000019.10:g.11106640G>A

CM000681.2:g.11106640G>A

NC_000019.9:g.11217316G>A

CM000681.1:g.11217316G>A

NC_000019.8:g.11078316G>A

NG_009060.1:g.22260G>A

ENST00000558518.6:c.770G>A

ENST00000252444.9:n.1024G>A

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

ENST00000535915.5:c.647G>A

ENST00000545707.5:c.389G>A

ENST00000557933.5:c.770G>A

ENST00000558013.5:c.770G>A

ENST00000558518.5:c.770G>A

ENST00000558528.1:n.285G>A

ENST00000560467.1:n.370G>A

NM_000527.4:c.770G>A

NM_001195798.1:c.770G>A

NM_001195799.1:c.647G>A

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

NM_001195803.1:c.389G>A

NM_001195798.2:c.770G>A

NM_001195799.2:c.647G>A

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

NM_001195803.2:c.389G>A

Uncertain Significance

PM2 BP4

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.770G>A (p.Arg257Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 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 - PopMax MAF = 0.00004395 (0.004395%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. BP4 - REVEL = 0.279, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create GT C) there are no GT nearby variant is predicted to not alter splicing, so BP4 is met.

PM2

PopMax MAF = 0.00004395 (0.004395%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

BP4

REVEL = 0.279, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create GT C) there are no GT nearby variant is predicted to not alter splicing, so BP4 is met.

BA1

FAF = 0.00001685 (0.001685%) in European non-Finnish exomes (gnomAD v2.1.1)

PM6

there is no report of this variant being identified de novo, so not met

PM3

there is no report 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>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

BS2

there is no report of this variant being identified in normolipidemi individuals, so not met

BS4

there is no segregation data, so not met

BS3

there is no functional study performed for this variant, so not met

BS1

FAF = 0.00001685 (0.001685%) in European non-Finnish exomes (gnomAD v2.1.1)

BP2

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

BP3

not applicable

BP1

not applicable

PVS1

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

BP5

not applicable

BP7

variant is missense, so not met

PS2

there is no report of this variant being identified de novo, so not met

PS4

Variant meets PM2, but there are no reports of this variant being identified in index cases who fulfill clinical FH criteria, so not met

PS3

there is no functional study performed for this variant, so not met

PS1

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

PP1

there is no segregation data, so not met

PP4

Variant meets PM2, but there are no reports of this variant being identified in index cases who fulfill clinical FH criteria, so not met

PP3

REVEL = 0.279, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create GT C) there are no GT nearby variant is predicted to not alter splicing, so PP3 is not met.

PP2

not applicable

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