Submissions for variant NM_144670.6(A2ML1):c.2173G>A (p.Glu725Lys)

gnomAD frequency: 0.00123  dbSNP: rs192221816

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000858102	SCV000556881	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000466084	SCV000716544	benign	not specified	2017-08-28	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	RCV000466084	SCV001363193	benign	not specified	2019-10-08	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.2173G>A (p.Glu725Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 248864 control chromosomes. The observed variant frequency is approximately 298 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.2173G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV000466084	SCV003912661	uncertain significance	not specified	2023-03-05	criteria provided, single submitter	clinical testing	The p.E725K variant (also known as c.2173G>A), located in coding exon 18 of the A2ML1 gene, results from a G to A substitution at nucleotide position 2173. The glutamic acid at codon 725 is replaced by lysine, an amino acid with 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.
PreventionGenetics, part of Exact Sciences	RCV003960058	SCV004772384	benign	A2ML1-related disorder	2019-09-27	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).