ClinVar Miner

Submissions for variant NM_145207.3(AFG2A):c.1622C>T (p.Pro541Leu)

dbSNP: rs143957561
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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 RCV000819737 SCV000960414 uncertain significance Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome 2018-10-04 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals with SPATA5-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. This variant is present in population databases (rs143957561, ExAC 0.009%). This sequence change replaces proline with leucine at codon 541 of the SPATA5 protein (p.Pro541Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
Ambry Genetics RCV004029013 SCV004868456 uncertain significance Inborn genetic diseases 2023-11-27 criteria provided, single submitter clinical testing The c.1622C>T (p.P541L) alteration is located in exon 9 (coding exon 9) of the AFG2A gene. This alteration results from a C to T substitution at nucleotide position 1622, causing the proline (P) at amino acid position 541 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/251432) total alleles studied. The highest observed frequency was 0.015% (5/34590) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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