Evidence Repository
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.967G>T (p.Gly323Cys)

CA16602321

375806 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: dbcd27a3-5bf2-491c-b76f-fc194354d4f8
Approved on: 2022-08-28
Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.967G>T
NM_000527.5(LDLR):c.967G>T (p.Gly323Cys)
NC_000019.10:g.11110678G>T
CM000681.2:g.11110678G>T
NC_000019.9:g.11221354G>T
CM000681.1:g.11221354G>T
NC_000019.8:g.11082354G>T
NG_009060.1:g.26298G>T
ENST00000558518.6:c.967G>T
ENST00000252444.9:n.1221G>T
ENST00000455727.6:c.463G>T
ENST00000535915.5:c.844G>T
ENST00000545707.5:c.586G>T
ENST00000557933.5:c.967G>T
ENST00000558013.5:c.967G>T
ENST00000558518.5:c.967G>T
ENST00000560467.1:n.541-836G>T
NM_000527.4:c.967G>T
NM_001195798.1:c.967G>T
NM_001195799.1:c.844G>T
NM_001195800.1:c.463G>T
NM_001195803.1:c.586G>T
NM_001195798.2:c.967G>T
NM_001195799.2:c.844G>T
NM_001195800.2:c.463G>T
NM_001195803.2:c.586G>T
More

Likely Pathogenic

Met criteria codes 5
PP4 PP1 PP3 PM2 PS4_Supporting
Not Met criteria codes 21
BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 BA1 PP2 PM6 PM3 PM1 PM4 PM5 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.967G>T (p.Gly323Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PS4_Supporting and PP4 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. PP1 - variant segregates with the FH phenotype in 2 informative meiosis (1 from each family) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 2 relatives with LDL>75th percentile have the variant, so PP1 is met. PP3 - REVEL = 0.903. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in 4 unrelated index cases who fulfill at least SB Possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), so PS4_Supporting is met PP4 - variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical criteria for FH after alternative causes for high cholesterol were excluded (please see PS4 for details), so PP4 is met.
Met criteria codes
PP4
variant meets PM2 and was identified in 4 unrelated index cases who fulfill at least SB Possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). so PP4 is met
PP1
variant segregates with the FH phenotype in 2 informative meiosis (1 from each family) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 2 relatives with LDL>75th percentile have the variant. so PP1 is met
PP3
REVEL = 0.903. It is above 0.75, so PP3 is met
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met
PS4_Supporting
variant meets PM2 and was identified in 4 unrelated index cases who fulfill at least SB Possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). so PS4_Supporting is met
Not Met criteria codes
BS4
there is no evidence of lack of segregation
BS3
There are no functional studies performed for this variant
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BS2
not identified in normolipidemic individuals, so not met
BP5
not applicable
BP7
variant is missense, so not applicable
BP2
variant was not identified in cases with more than 1 variant
BP3
not applicable
BP4
REVEL = 0.903. It is not below 0.50, so BP4 is not met
BP1
not applicable
PS2
no de novo occurrence
PS3
There are no functional studies performed for this variant
PS1
no other missense variant leads to the same amino acid change, so not met
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
PP2
not applicable
PM6
no de novo occurrence
PM3
variant was not identified in cases with more than 1 variant
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 applicable
PM5
1 other missense variant in the same codon: - NM_000527.5(LDLR):c.967G>A (p.Gly323Ser) - classified as Uncertain significance by the FH VCEP so PM5 is not met
PVS1
variant is missense and not in initiation codon, so not applicable
Curation History
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