Submissions for variant NM_144670.6(A2ML1):c.462+9GGA[2]

dbSNP: rs750639846

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514252	SCV000610404	likely benign	not provided	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193880	SCV001363038	benign	not specified	2019-11-11	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.462+16_462+18delGAG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 249488 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is more than 300 higher than the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.462+16_462+18delGAG in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its 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 benign.
Invitae	RCV000514252	SCV001728585	benign	not provided	2024-01-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514252	SCV004698410	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	A2ML1: BS2