ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1120G>C (p.Asp374His)

dbSNP: rs137852912
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000256334 SCV000323062 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles (portuguese normolipidemic individuals)
Labcorp Genetics (formerly Invitae), Labcorp RCV001859495 SCV002246437 pathogenic Hypercholesterolemia, autosomal dominant, 3 2021-02-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCSK9 protein function. Experimental studies have shown that this variant affects PCSK9 protein function (PMID: 22875854, 19081568, 26195630). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 17765246, 26374825, Invitae). ClinVar contains an entry for this variant (Variation ID: 265939). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 374 of the PCSK9 protein (p.Asp374His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine.

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