Submissions for variant NM_144670.6(A2ML1):c.2249A>C (p.Glu750Ala)

gnomAD frequency: 0.00080  dbSNP: rs200618482

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000609965	SCV000714731	benign	not specified	2017-11-28	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000861745	SCV001002139	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000609965	SCV001337855	benign	not specified	2020-01-27	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.2249A>C (p.Glu750Ala) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 249448 control chromosomes, predominantly at a frequency of 0.0027 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 675 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.2249A>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV000609965	SCV003912669	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	The p.E750A variant (also known as c.2249A>C), located in coding exon 19 of the A2ML1 gene, results from an A to C substitution at nucleotide position 2249. The glutamic acid at codon 750 is replaced by alanine, an amino acid with dissimilar 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.
CeGaT Center for Human Genetics Tuebingen	RCV000861745	SCV004134390	benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	A2ML1: BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000861745	SCV005213744	likely benign	not provided		criteria provided, single submitter	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000861745	SCV002037247	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000861745	SCV002037993	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945465	SCV004767900	benign	A2ML1-related disorder	2019-09-06	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).