The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


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

CA358775

225181 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
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
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Uncertain Significance

Met criteria codes 2
PP3 PM2
Not Met criteria codes 24
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

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

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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.
Met criteria codes
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
Not Met criteria codes
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
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