Submissions for variant NM_144670.6(A2ML1):c.158C>G (p.Thr53Arg)

gnomAD frequency: 0.00207  dbSNP: rs79149293

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000514223	SCV000556875	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514223	SCV000609824	likely benign	not provided	2017-06-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000514223	SCV000808466	benign	not provided	2020-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193834	SCV001362974	benign	not specified	2019-08-26	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.158C>G (p.Thr53Arg) results in a non-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 0.0021 in 249546 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 850 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.158C>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000514223	SCV001956837	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000514223	SCV001962938	likely benign	not provided		no assertion criteria provided	clinical testing