ClinVar Miner

Submissions for variant NM_144670.6(A2ML1):c.4261C>T (p.Gln1421Ter)

gnomAD frequency: 0.00009  dbSNP: rs182070540
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000863900 SCV001004629 likely benign not provided 2024-01-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201231 SCV001372324 benign not specified 2020-06-22 criteria provided, single submitter clinical testing Variant summary: A2ML1 c.4261C>T (p.Gln1421X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which is not commonly known mechanisms for NSRD. The variant allele was found at a frequency of 0.00024 in 249460 control chromosomes. The observed variant frequency is approximately 60 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome And Related Conditions phenotype (4e-06), strongly suggesting that the variant is benign. c.4261C>T has been reported in the literature in individuals affected with RASopathies (Leung_2018). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Leung_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

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