Submissions for variant NM_144670.6(A2ML1):c.1745A>G (p.Gln582Arg)

gnomAD frequency: 0.00225  dbSNP: rs200271507

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469902	SCV000556893	benign	not provided	2023-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255523	SCV001431970	benign	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.1745A>G (p.Gln582Arg) 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 0.0005 in 248684 control chromosomes, predominantly at a frequency of 0.0071 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1800-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 African or African-American origin. To our knowledge, no occurrence of c.1745A>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000469902	SCV001902145	benign	not provided	2019-09-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001255523	SCV003912664	uncertain significance	not specified	2023-01-18	criteria provided, single submitter	clinical testing	The p.Q582R variant (also known as c.1745A>G), located in coding exon 15 of the A2ML1 gene, results from an A to G substitution at nucleotide position 1745. The glutamine at codon 582 is replaced by arginine, 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.
PreventionGenetics, part of Exact Sciences	RCV003925340	SCV004741472	benign	A2ML1-related disorder	2020-01-06	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).