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.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

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

Pathogenic

PVS1 PP4 PM3 PM2 PS4_Moderate PP1_Strong

BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 BA1 PP3 PP2 PM1 PM4 PM5 PM6 BS4 BS3 BS1 BS2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

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.

PVS1

variant is nonsense, causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830), so PVS1 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

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

PM2

PopMax MAF = 0.00003267 (0.003%) in South asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

PS4_Moderate

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

BP5

not applicable

BP7

variant is nonsense, so not applicable

BP2

no other variants identified in index cases

BP3

not applicable

BP4

PVS1 is met, so BP4 is not applicable

BP1

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

PP3

PVS1 is met, so PP3 is not applicable

PP2

not applicable

PM1

variant is nonsense, so not applicable

PM4

variant is nonsense, so not applicable

PM5

variant is nonsense, so not applicable

PM6

no de novo occurence

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

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

Approved on: 2022-08-28

Published on: 2022-08-28

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