Submissions for variant NM_144670.6(A2ML1):c.3124A>G (p.Thr1042Ala)

dbSNP: rs565930773

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000874250	SCV001016393	likely benign	not provided	2024-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193877	SCV001363035	benign	not specified	2019-12-09	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.3124A>G (p.Thr1042Ala) results in a non-conservative amino acid change located in the Alpha-macroglobulin-like, TED domain (IPR011626) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 249426 control chromosomes, predominantly at a frequency of 0.0036 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 900 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. To our knowledge, no occurrence of c.3124A>G 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.
Department of Human Genetics, University Hospital Magdeburg	RCV001193877	SCV001372224	likely benign	not specified	2020-07-09	criteria provided, single submitter	clinical testing	For this variant in-silico prediction yielded a consistent neutral prediction on the gene function (PB4). The variant was found to be inherited by the presumably affected index patient's father, but allele frequency of the variant was higher than expected for Noonan syndrome (BS1), which is why we classify this variant as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003938340	SCV004747438	likely benign	A2ML1-related condition	2022-04-06	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).