Submissions for variant NM_025215.6(PUS1):c.841G>A (p.Val281Met)

gnomAD frequency: 0.00002  dbSNP: rs776626629

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196036	SCV000252153	uncertain significance	not provided	2015-07-29	criteria provided, single submitter	clinical testing	p.Val281Met (GTG>ATG): c.841 G>A in exon 5 of the PUS1 gene (NM_025215.5) A variant of unknown significance has been identified in the PUS1 gene. The V281M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V281M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids similar to Valine are conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Illumina Laboratory Services, Illumina	RCV001113697	SCV001271488	uncertain significance	Myopathy, lactic acidosis, and sideroblastic anemia 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000196036	SCV002121301	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 281 of the PUS1 protein (p.Val281Met). This variant is present in population databases (rs776626629, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with PUS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 215050). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Natera, Inc.	RCV001113697	SCV001459549	uncertain significance	Myopathy, lactic acidosis, and sideroblastic anemia 1	2020-03-10	no assertion criteria provided	clinical testing