Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000237103 | SCV004022443 | likely benign | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1185G>C (p.Val395=) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4 and BP7) 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). BP4 - No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -3 to +6 bases of canonical donor splicing site. MES scores: de novo donor = 9.1, authentic donor = 7.23. Ratio variant/wt = 1.26. It is above 1.0. Score >= 1.0 is supportive evidence of benign. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met. BP7 - Variant is synonymous and meets BP4. |
LDLR- |
RCV000237103 | SCV000295262 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000237103 | SCV000322936 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | 0/75 normolipidaemic Portuguese controls |
Invitae | RCV003741174 | SCV004374237 | uncertain significance | Familial hypercholesterolemia | 2023-02-02 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 251702). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 19411563). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 395 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237103 | SCV000606342 | benign | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |