ClinVar Miner

Submissions for variant NM_176787.5(PIGN):c.2679C>G (p.Ser893Arg) (rs199573774)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519462 SCV000616821 likely pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing The S893R variant in the PIGN gene has been reported as likely pathogenic in an individual who had clinical exome sequencing; however, no additional clinical or segregation information was provided in the publication, but S893R has been identified as compound heterozygous or homozygous in patients tested at GeneDx who had features consistent with PIGN-related disorder (Retterer et al., 2016). In addition, S893R was reported in an abstract by Reynoso et al. (2016), the S893R variant was identified in the apparently compound heterozygous state with a second PIGN variant in a patient with hypotonia, intractable seizures, and congenital anomalies. The S893R variant is observed in 13/30170 (0.04%) alleles from individuals of South Asian background and 50/274238 (0.02%) total alleles in large population cohorts (Lek et al., 2016). The S893R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S893R as a likely pathogenic variant.
Invitae RCV000706539 SCV000835596 uncertain significance Multiple congenital anomalies-hypotonia-seizures syndrome 1 2017-10-17 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 893 of the PIGN protein (p.Ser893Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs199573774, ExAC 0.04%). This variant has not been reported in the literature in individuals with PIGN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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