Submissions for variant NM_174936.4(PCSK9):c.1130C>G (p.Thr377Ser)

dbSNP: rs760947578

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176336	SCV001340279	uncertain significance	Familial hypercholesterolemia	2022-10-24	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 377 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 2/251032 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003500643	SCV004267035	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 377 of the PCSK9 protein (p.Thr377Ser). This variant is present in population databases (rs760947578, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. ClinVar contains an entry for this variant (Variation ID: 918637). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCSK9 protein function. 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.
All of Us Research Program, National Institutes of Health	RCV003500643	SCV004836530	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 377 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 2/251032 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV004812384	SCV005437355	uncertain significance	not provided	2024-06-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge