ClinVar Miner

Submissions for variant NM_144670.6(A2ML1):c.277G>T (p.Val93Leu)

gnomAD frequency: 0.00014  dbSNP: rs775011475
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000983939 SCV001131989 likely benign not provided 2024-12-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255531 SCV001431987 likely benign not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: A2ML1 c.277G>T (p.Val93Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249478 control chromosomes, predominantly at a frequency of 0.00096 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 240 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.277G>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV001255531 SCV002746345 uncertain significance not specified 2023-12-11 criteria provided, single submitter clinical testing The p.V93L variant (also known as c.277G>T), located in coding exon 3 of the A2ML1 gene, results from a G to T substitution at nucleotide position 277. The valine at codon 93 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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