ClinVar Miner

Submissions for variant NM_000209.4(PDX1):c.107T>G (p.Leu36Arg)

dbSNP: rs936861677
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002020957 SCV002300053 uncertain significance not provided 2022-08-16 criteria provided, single submitter clinical testing The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 36 of the PDX1 protein (p.Leu36Arg). This variant has not been reported in the literature in individuals affected with PDX1-related conditions. 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. 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 expected to disrupt PDX1 protein function. ClinVar contains an entry for this variant (Variation ID: 1515252).
New York Genome Center RCV002468380 SCV002764411 uncertain significance Maturity-onset diabetes of the young type 4; Type 2 diabetes mellitus 2021-10-18 criteria provided, single submitter clinical testing The heterozygous c.107T>G (p.Leu36Arg) variant identified in the PDX1 gene substitutes a very well conserved Leucine for Arginine at amino acid36/283 (exon 1/2). This variant is absent from gnomAD(v3.1.1) and is found with low frequency in gnomAD(v2.1.1) (1 out 139702 heterozygous alleles, 0 homozygotes; allele frequency: 0.000007158) suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be Tolerated (SIFT; score: 0.078) and Pathogenic (REVEL; score: 0.7369) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the c.107T>G(p.Leu36Arg) variant identified in the PDX1 gene is reported as a Variant of Uncertain Significance.

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