Submissions for variant NM_144670.6(A2ML1):c.174_175dup (p.Lys59fs)

gnomAD frequency: 0.00051  dbSNP: rs745711489

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000281991	SCV000337477	uncertain significance	not provided	2015-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000281991	SCV001002273	likely benign	not provided	2024-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532916	SCV001748717	benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.174_175dupCA (p.Lys59ThrfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00011 in 249560 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 450 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 African or African-American origin. To our knowledge, no occurrence of c.174_175dupCA in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000281991	SCV001866373	benign	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000281991	SCV004238821	uncertain significance	not provided	2020-06-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947885	SCV004766144	likely benign	A2ML1-related disorder	2022-03-10	no assertion criteria provided	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).