ClinVar Miner

Submissions for variant NM_000301.5(PLG):c.646G>A (p.Ala216Thr)

gnomAD frequency: 0.00006  dbSNP: rs374234922
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV002493827 SCV002806234 uncertain significance Plasminogen deficiency, type I; Angioedema, hereditary, 4 2021-12-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001356493 SCV004677419 uncertain significance not provided 2024-04-02 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 216 of the PLG protein (p.Ala216Thr). This variant is present in population databases (rs374234922, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049859). 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 not expected to disrupt PLG protein function with a negative predictive value of 95%. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356493 SCV001551680 uncertain significance not provided no assertion criteria provided clinical testing The PLG p.Ala216Thr variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs374234922) and in control databases in 13 of 282524 chromosomes at a frequency of 0.000046 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 3 of 10362 chromosomes (freq: 0.00029), Other in 2 of 7210 chromosomes (freq: 0.000277), African in 3 of 24960 chromosomes (freq: 0.00012), East Asian in 1 of 19924 chromosomes (freq: 0.00005) and European (non-Finnish) in 4 of 128942 chromosomes (freq: 0.000031); it was not observed in the Latino, European (Finnish), and South Asian populations. The p.Ala216 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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