ClinVar Miner

Submissions for variant NM_013335.4(GMPPA):c.592T>C (p.Phe198Leu)

dbSNP: rs773715630
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000535177 SCV000654690 uncertain significance Alacrima, achalasia, and intellectual disability syndrome 2018-01-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 198 of the GMPPA protein (p.Phe198Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs773715630, ExAC 0.1%) but has not been reported in the literature in individuals with a GMPPA-related disease. In summary, this variant is a rare missense change with uncertain impact on protein function.  There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0").
Ambry Genetics RCV003278914 SCV004007669 uncertain significance Inborn genetic diseases 2023-04-05 criteria provided, single submitter clinical testing The c.592T>C (p.F198L) alteration is located in exon 7 (coding exon 6) of the GMPPA gene. This alteration results from a T to C substitution at nucleotide position 592, causing the phenylalanine (F) at amino acid position 198 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM RCV000535177 SCV004047367 uncertain significance Alacrima, achalasia, and intellectual disability syndrome criteria provided, single submitter clinical testing The missense variant c.592T>C (p.Phe198Leu) in GMPPA has been submitted to ClinVar as Variant of Uncertain Significance (VUS). The p.Phe198Leu variant has allele frequency of 0.013% in the gnomad and novel (not in any individuals) in 1000 genome database. The amino acid Phe at position 198 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe198Leu in GMPPA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).
3billion, Medical Genetics RCV000535177 SCV005328665 likely benign Alacrima, achalasia, and intellectual disability syndrome 2024-09-20 criteria provided, single submitter clinical testing The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.

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