Submissions for variant NM_144670.6(A2ML1):c.3903G>C (p.Glu1301Asp)

gnomAD frequency: 0.00138  dbSNP: rs77431272

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000858359	SCV000291418	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000226363	SCV000714833	benign	not specified	2017-05-19	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	RCV000226363	SCV001360889	benign	not specified	2019-12-30	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.3903G>C (p.Glu1301Asp) results in a conservative amino acid change in 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 0.00027 in 249334 control chromosomes. The observed variant frequency is approximately 67 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.3903G>C 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 (n=1)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV000226363	SCV003912671	uncertain significance	not specified	2023-02-19	criteria provided, single submitter	clinical testing	The p.E1301D variant (also known as c.3903G>C), located in coding exon 30 of the A2ML1 gene, results from a G to C substitution at nucleotide position 3903. The glutamic acid at codon 1301 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV000858359	SCV005213755	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003955374	SCV004771392	likely benign	A2ML1-related disorder	2022-03-21	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).