Submissions for variant NM_144670.6(A2ML1):c.2405G>A (p.Arg802His)

gnomAD frequency: 0.00013  dbSNP: rs201562272

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000185643	SCV000556886	likely benign	not provided	2024-01-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000185643	SCV000574918	uncertain significance	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Department of Human Genetics, University Hospital Magdeburg	RCV001201332	SCV001372221	benign	not specified	2020-07-09	criteria provided, single submitter	clinical testing	This variant has been previously published as a causal variant for a disorder resembling Noonan syndrome by Vissers et al (2015). The allele frequency of this variant in gnomAD is greater than expected for Noonan syndrome (5.98e-4) (BS1). In-silico prediction yields consistent gene function affecting result (PP3). The variant was once found in a patient harbouring a known causal RAF1 variant and once in a patient harbouring a known causal MAP2K1 variant, fully explaining the phenotypes in both patients (BP5). Additionally, the variant was found to be inherited by the index patient's unaffected father in one case (BS2).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201332	SCV001478738	likely benign	not specified	2021-01-21	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.2405G>A (p.Arg802His) results in a non-conservative amino acid change located in the Alpha-2-macroglobulin domain (IPR001599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 249558 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 375 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 South Asian origin. c.2405G>A has been reported in the literature in individuals affected with Noonan Syndrome, including one de novo occurrence (Vissers_2015, Tidyman_2016, Brinkmann_2020). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (RAF1 c.770C>T , p.Ser257Leu; MAP2K1 c.275T>G, p.Leu92Arg) (Brinkmann_2020), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Vissers_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000185643	SCV000238559	uncertain significance	not provided	2015-03-01	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001251215	SCV001426701	likely benign	Noonan syndrome		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003937655	SCV004764733	likely benign	A2ML1-related disorder	2019-11-21	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).