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.1176C>A (p.Cys392Ter)

CA032391

251699 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 14063be8-c4fc-4a79-b1f5-70d2fa4071ca
Approved on: 2022-08-28
Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.1176C>A
NM_000527.5(LDLR):c.1176C>A (p.Cys392Ter)
NC_000019.10:g.11111629C>A
CM000681.2:g.11111629C>A
NC_000019.9:g.11222305C>A
CM000681.1:g.11222305C>A
NC_000019.8:g.11083305C>A
NG_009060.1:g.27249C>A
ENST00000558518.6:c.1176C>A
ENST00000252444.9:n.1430C>A
ENST00000455727.6:c.672C>A
ENST00000535915.5:c.1053C>A
ENST00000545707.5:c.795C>A
ENST00000557933.5:c.1176C>A
ENST00000558013.5:c.1176C>A
ENST00000558518.5:c.1176C>A
ENST00000560173.1:n.175C>A
ENST00000560467.1:n.656C>A
NM_000527.4:c.1176C>A
NM_001195798.1:c.1176C>A
NM_001195799.1:c.1053C>A
NM_001195800.1:c.672C>A
NM_001195803.1:c.795C>A
NM_001195798.2:c.1176C>A
NM_001195799.2:c.1053C>A
NM_001195800.2:c.672C>A
NM_001195803.2:c.795C>A
More

Pathogenic

Met criteria codes 6
PP1_Strong PVS1 PM2 PM3 PP4 PS4_Moderate
Not Met criteria codes 20
BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS3 PS1 BA1 PM6 PM1 PM4 PM5 PP3 PP2 BS2 BS4 BS3 BS1

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.1176C>A (p.Cys392Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PM2, PM3, PS4_Moderate 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: PVS1 - variant is nonsense, causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830), so PVS1 is met. PP1_strong - variant segregates with FH phenotype in: - 7 informative meiosis from 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 4 relatives positive for variant with LDL-C >75th percentile, and 3 relatives negative for variant with LDL-C <50th percentile. - 1 informative meiosis from 1 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): 1 relative positive for variant with LDL-C >75th percentile. - 11 informative meiosis from 1 family from PMID: 8831933 (Langenhoven et al. 1996): 11 relatives are positive for the variant and have LDL-C >75th percentile (9 have >5.0mmol, 2 have 4.6 and 4.3mmol) Segregation was observed in 19 informative meiosis from 3 families, so PP1_Strong is met. PM2 - PopMax MAF = 0.00003267 (0.003%) in South asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM3 - variant meets PM2 and was identified in 1 index case who also carries NM_000527.5(LDLR):c.1A>T (p.Met1Leu), confirmed in trans, who has LDL 17.3mmol/L from PMID: 8831933 (Langenhoven et al. 1996 Aug 23;125(1):111-9. --- 2nd variant is classified as Pathogenic with these guidelines, so PM3 is met. PS4_moderate - variant meets PM2 and was identified in: - 1 index case who fulfills Simon-Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 1 index case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 4 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada; - 1 Index case (iii-4) with DLCN at least 8 (LDL-C 17.3mmol at 4yo with tendon xanthoma) from PMID: 8831933 (Langenhoven et al. 1996), South Africa; - 1 index case with heterozygous FH per MEDPED criteria from PMID: 11933210 (Salazar et al. 2002), Brazil; - at least 1 index case with definite FH ("definite heterozygous FH by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 11810272 (Fouchier et al. 2001), The Netherlands. 9 unrelated cases, so PS4_Moderate is met. PP4 - variant meets PM2 and was identified in 9 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is met.
Met criteria codes
PP1_Strong
variant segregates with FH phenotype in: - 7 informative meiosis from 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 4 relatives positive for variant with LDL-C >75th percentile, and 3 relatives negative for variant with LDL-C <50th percentile. - 1 informative meiosis from 1 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): 1 relative positive for variant with LDL-C >75th percentile. - 11 informative meiosis from 1 family from PMID: 8831933 (Langenhoven et al. 1996): 11 relatives are positive for the variant and have LDL-C >75th percentile (9 have >5.0mmol, 2 have 4.6 and 4.3mmol) Segregation was observed in 19 informative meiosis from 3 families, so PP1_Strong is met
PVS1
variant is nonsense, causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830), so PVS1 is met
PM2
PopMax MAF = 0.00003267 (0.003%) in South asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met
PM3
variant meets PM2 and was identified in 1 index case who also carries NM_000527.5(LDLR):c.1A>T (p.Met1Leu), confirmed in trans, who has LDL 17.3mmol/L from PMID: 8831933 (Langenhoven et al. 1996 Aug 23;125(1):111-9. --- 2nd variant is classified as Pathogenic with these guidelines, so PM3 is met
PP4
variant meets PM2 and was identified in - 1 index case who fulfills Simon-Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 1 index case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 4 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada; - 1 Index case (iii-4) with DLCN at least 8 (LDL-C 17.3mmol at 4yo with tendon xanthoma) from PMID: 8831933 (Langenhoven et al. 1996), South Africa; - 1 index case with heterozygous FH per MEDPED criteria from PMID: 11933210 (Salazar et al. 2002), Brazil; - at least 1 index case with definite FH ("definite heterozygous FH by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 11810272 (Fouchier et al. 2001), The Netherlands. so PP4 is met
PS4_Moderate
variant meets PM2 and was identified in - 1 index case who fulfills Simon-Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 1 index case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 4 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada; - 1 Index case (iii-4) with DLCN at least 8 (LDL-C 17.3mmol at 4yo with tendon xanthoma) from PMID: 8831933 (Langenhoven et al. 1996), South Africa; - 1 index case with heterozygous FH per MEDPED criteria from PMID: 11933210 (Salazar et al. 2002), Brazil; - at least 1 index case with definite FH ("definite heterozygous FH by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 11810272 (Fouchier et al. 2001), The Netherlands. 9 unrelated cases, so PS4_Moderate is met
Not Met criteria codes
BP2
no other variants identified in index cases
BP3
not applicable
BP4
PVS1 is met, so BP4 is not applicable
BP1
not applicable
BP5
not applicable
BP7
variant is nonsense, so not applicable
PS2
no de novo occurence
PS3
there is no published functional study on this variant
PS1
variant is nonsense, so not applicable
BA1
no FAF, just total MAF = 0.000003990 (0.0004%) in South asian exomes (gnomAD v2.1.1). It is not above 0.5%, so BA1 is not met
PM6
no de novo occurence
PM1
variant is nonsense, so not applicable
PM4
variant is nonsense, so not applicable
PM5
variant is nonsense, so not applicable
PP3
PVS1 is met, so PP3 is not applicable
PP2
not applicable
BS2
variant not identified in normolipidemic individuals: 0/200 non-FH alleles from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge and 0/1000 normolipidemic individuals from Robarts Research Institute, so BS2 is not met
BS4
There was lack of segregation observed in: - 1 informative meiosis from 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative negative for variant with LDL-C >75th percentile. it is not enough, so BS4 is not met
BS3
there is no published functional study on this variant
BS1
no FAF, just total MAF = 0.000003990 (0.0004%) in South asian exomes (gnomAD v2.1.1). It is not above 0.2%, so BS1 is not met
Curation History
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