ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.977C>T (p.Ser326Phe)

dbSNP: rs879254747
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237746 SCV002506341 likely pathogenic Hypercholesterolemia, familial, 1 2022-01-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.977C>T (p.Ser326Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3 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. PM5 - There are 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) - 2 stars, Likely pathogenic in ClinVar; Pathogenic by these guidelines (FH VCEP training August 2020). (2) NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) - 1 star, VUS in ClinVar; VUS by these guidelines (PM2, PM5, PP3) with no case data. There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is met PP3 - REVEL = 0.937. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case who fulfills SB criteria (clinical criteria according to PMID 8891383 (Chaves et al., 1996): TC and LDL-C over the 95th percentile corrected for age and sex, with TG not exceeding 200 mg/dl; plus two of the following: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative, and hypercholesterolemic children in the family) from PMID 11668640 (García-García et al. 2001), Spain; so PP4 is met
LDLR-LOVD, British Heart Foundation RCV000237746 SCV000295123 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only

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