Submissions for variant NM_144670.6(A2ML1):c.3392C>T (p.Thr1131Met)

gnomAD frequency: 0.01340  dbSNP: rs7959680

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000858199	SCV000291414	benign	not provided	2025-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000231779	SCV000714196	benign	not specified	2017-05-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000231779	SCV001363200	benign	not specified	2019-09-30	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.3392C>T (p.Thr1131Met) results in a non-conservative amino acid change located in the Alpha-macroglobulin like TET domain (IPRO11626) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 249544 control chromosomes in the gnomAD database, including 16 homozygotes. The observed variant frequency is approximately 919 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 benign. To our knowledge, no occurrence of c.3392C>T 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. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000231779	SCV001919938	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000231779	SCV001959312	benign	not specified		no assertion criteria provided	clinical testing