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.1004G>A (p.Gly335Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA358775

225181 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 6a128f31-00cd-4fea-a119-af03bcb1840d

Approved on: 2023-04-28

Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1004G>A

NM_000527.5(LDLR):c.1004G>A (p.Gly335Asp)

NC_000019.10:g.11110715G>A

CM000681.2:g.11110715G>A

NC_000019.9:g.11221391G>A

CM000681.1:g.11221391G>A

NC_000019.8:g.11082391G>A

NG_009060.1:g.26335G>A

ENST00000252444.10:c.1262G>A

ENST00000559340.2:c.1004G>A

ENST00000560467.2:c.941-799G>A

ENST00000558518.6:c.1004G>A

ENST00000252444.9:c.1258G>A

ENST00000455727.6:c.500G>A

ENST00000535915.5:c.881G>A

ENST00000545707.5:c.623G>A

ENST00000557933.5:c.1004G>A

ENST00000558013.5:c.1004G>A

ENST00000558518.5:c.1004G>A

ENST00000560173.1:n.3G>A

ENST00000560467.1:c.541-799G>A

NM_000527.4:c.1004G>A

NM_001195798.1:c.1004G>A

NM_001195799.1:c.881G>A

NM_001195800.1:c.500G>A

NM_001195803.1:c.623G>A

NM_001195798.2:c.1004G>A

NM_001195799.2:c.881G>A

NM_001195800.2:c.500G>A

NM_001195803.2:c.623G>A

Uncertain Significance

PP3 PM2

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

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.1004G>A (p.Gly335Asp) 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 = 0.00001762 (0.001762%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.857. It is above 0.75, so PP3 is met.

PP3

REVEL = 0.857. It is above 0.75, so PP3 is met

PM2

PopMax MAF = 0.00001762 (0.001762%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

BS2

variant was not identified in normolipidemic individuals, so not met

BS1

FAF = 0.000002930 (0.0003%) in European non-Finnish exomes (gnomAD v2.1.1). It is not above 0.2%, so not met

BS4

no segregation data

BS3

there are no published functional studies

BP5

not applicable

BP7

not applicable

BP4

REVEL = 0.857. It is not below 0.50, so BP4 is not met

BP3

not applicable

BP1

not applicable

BP2

no case data

BA1

FAF = 0.000002930 (0.0003%) in European non-Finnish exomes (gnomAD v2.1.1). It is not above 0.5%, so not met

PS1

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

PS2

no case data

PS3

there are no published functional studies

PS4

no case data

PP1

no segregation data

PP2

not applicable

PP4

no case data

PVS1

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

PM6

no case data

PM1

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

PM3

no case data

PM5

There are 4 other missense variants in the same codon: NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys) - classified as Likely pathogenic by these guidelines NM_000527.5(LDLR):c.1004G>T (p.Gly335Val) - classified as VUS by these guidelines NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) - classified as Likely pathogenic by these guidelines NM_000527.5(LDLR):c.1003G>C (p.Gly335Arg) - classified as VUS by these guidelines No variant classified as Pathogenic in the same codon, so not met

PM4

variant is missense, so not met

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.