ClinVar Miner

Submissions for variant NM_198576.4(AGRN):c.4120G>T (p.Val1374Leu)

dbSNP: rs1057523585
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000438345 SCV000532615 uncertain significance not provided 2016-10-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the AGRN gene. The V1374L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although the V1374L variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the data was noted to have reduced depth of sequencing reads and therefore may be unreliable. The V1374L 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 with similar properties to Valine are tolerated across species and in silico analysis predicts this variant likely does not alter the protein structure/function. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001066019 SCV001231012 uncertain significance Congenital myasthenic syndrome 8 2019-02-08 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1374 of the AGRN protein (p.Val1374Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with AGRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 389927). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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