Submissions for variant NM_144670.6(A2ML1):c.3878A>G (p.Asn1293Ser)

gnomAD frequency: 0.00061  dbSNP: rs201478459

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000471495	SCV000556896	likely benign	not provided	2024-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193873	SCV001363031	benign	not specified	2019-10-21	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.3878A>G (p.Asn1293Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 249424 control chromosomes, predominantly at a frequency of 0.00091 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 228 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 Non-Finnish European origin. To our knowledge, no occurrence of c.3878A>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. 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.
GeneDx	RCV000471495	SCV001858450	likely benign	not provided	2019-09-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24939586)
PreventionGenetics, part of Exact Sciences	RCV003902667	SCV004719151	likely benign	A2ML1-related condition	2023-08-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000471495	SCV001957740	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000471495	SCV001966597	likely benign	not provided		no assertion criteria provided	clinical testing