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.1003G>C (p.Gly335Arg)

CA031125

926520 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 6a8b1152-d237-4e6d-9b68-35944e862410

Approved on: 2023-04-28

Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1003G>C

NM_000527.5(LDLR):c.1003G>C (p.Gly335Arg)

NC_000019.10:g.11110714G>C

CM000681.2:g.11110714G>C

NC_000019.9:g.11221390G>C

CM000681.1:g.11221390G>C

NC_000019.8:g.11082390G>C

NG_009060.1:g.26334G>C

ENST00000558518.6:c.1003G>C

ENST00000252444.9:n.1257G>C

ENST00000455727.6:c.499G>C

ENST00000535915.5:c.880G>C

ENST00000545707.5:c.622G>C

ENST00000557933.5:c.1003G>C

ENST00000558013.5:c.1003G>C

ENST00000558518.5:c.1003G>C

ENST00000560173.1:n.2G>C

ENST00000560467.1:n.541-800G>C

NM_000527.4:c.1003G>C

NM_001195798.1:c.1003G>C

NM_001195799.1:c.880G>C

NM_001195800.1:c.499G>C

NM_001195803.1:c.622G>C

NM_001195798.2:c.1003G>C

NM_001195799.2:c.880G>C

NM_001195800.2:c.499G>C

NM_001195803.2:c.622G>C

Uncertain Significance

PM2 PP3

PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS4 PS3 PS1 PM3 PM1 PM4 PM5 PM6 BA1 PP4 PP1 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_000527.4(LDLR):c.1003G>C (p.(Gly335Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 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 = 0.000008813 (0.0009%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. - PP3 : REVEL = 0.901. It is above 0.75, so PP3 is met.

PM2

PopMax MAF = 0.000008813 (0.0009%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

PP3

REVEL = 0.901. It is above 0.75, so PP3 is met

PVS1

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

BS2

variant was not identified in normolipidemic individuals, so not met

BS4

no segregation data available, so not met

BS3

no functional studies published

BS1

no FAF, just total MAF = 0.000003984 (0.0004%) (gnomAD v2.1.1). It is above 0.5%, so not met

BP2

no case data, so not met

BP3

not applicable

BP4

REVEL = 0.901. It is not below 0.50, so BP4 is not met

BP1

not applicable

BP5

not applicable

BP7

variant is missense, so not applicable

PS2

no de novo cases identified, so not met

PS4

no case data available, so not met

PS3

no functional studies published

PS1

no other missense variant leads to the same amino acid change, so not met

PM3

no case data, so not met

PM1

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

PM4

variant is missense, so not applicable

PM5

There are 4 other missense variants in the same codon: NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys) - classified as Likely pathogenic with these guidelines NM_000527.5(LDLR):c.1004G>T (p.Gly335Val) - classified as VUS with these guidelines NM_000527.5(LDLR):c.1004G>A (p.Gly335Asp) - classified as VUS with these guidelines NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) - classified as Likely pathogenic with these guidelines. No Pathogenic variant in the same codon, so not met

PM6

no de novo cases identified, so not met

BA1

no FAF, just total MAF = 0.000003984 (0.0004%) (gnomAD v2.1.1). It is above 0.5%, so not met

PP4

no case data, so not met

PP1

no segregation data available, so not met

PP2

not applicable

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