ClinVar Miner

Submissions for variant NM_000514.4(GDNF):c.633C>G (p.Ile211Met)

gnomAD frequency: 0.00011  dbSNP: rs121918536
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004766993 SCV005380404 uncertain significance not specified 2024-08-22 criteria provided, single submitter clinical testing Variant summary: GDNF c.633C>G (p.Ile211Met) results in a conservative amino acid change located in the Transforming growth factor-beta, C-terminal domain (IPR001839) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251428 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GDNF causing Hirschsprung Disease, Susceptibility To, 3, allowing no conclusion about variant significance. c.633C>G has been reported in the literature in individuals affected with Hirschsprung Disease and Kidney and/or genitourinary disorder (example, Martucciello_2000, Rasouly_2019), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hirschsprung Disease, Susceptibility To, 3. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Eketjall_2002). The following publications have been ascertained in the context of this evaluation (PMID: 11823451, 10917288, 26489027, 30476936). ClinVar contains an entry for this variant (Variation ID: 8761). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM RCV000009306 SCV000029524 risk factor Hirschsprung disease, susceptibility to, 3 2000-07-01 no assertion criteria provided literature only

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