ClinVar Miner

Submissions for variant NM_144670.6(A2ML1):c.1991C>T (p.Ser664Leu)

gnomAD frequency: 0.00001  dbSNP: rs187676229
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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 RCV001174682 SCV001337915 uncertain significance not specified 2020-01-06 criteria provided, single submitter clinical testing Variant summary: A2ML1 c.1991C>T (p.Ser664Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249046 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1991C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating an impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003558743 SCV004284852 uncertain significance not provided 2024-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 664 of the A2ML1 protein (p.Ser664Leu). This variant is present in population databases (rs187676229, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with A2ML1-related conditions. ClinVar contains an entry for this variant (Variation ID: 917607). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

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