Submissions for variant NM_144670.6(A2ML1):c.863A>G (p.Lys288Arg)

gnomAD frequency: 0.00252  dbSNP: rs75617691

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000858616	SCV000556879	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000471264	SCV000717234	benign	not specified	2017-06-15	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	RCV000471264	SCV001370691	benign	not specified	2020-05-26	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.863A>G (p.Lys288Arg) results in a conservative amino acid change located in the Macroglobulin domain MG3 (IPR041555) of 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 0.00069 in 248992 control chromosomes, predominantly at a frequency of 0.0099 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 2475 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome And Related Conditions 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.863A>G in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV000471264	SCV002688488	uncertain significance	not specified	2022-10-27	criteria provided, single submitter	clinical testing	The p.K288R variant (also known as c.863A>G), located in coding exon 9 of the A2ML1 gene, results from an A to G substitution at nucleotide position 863. The lysine at codon 288 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.
Breakthrough Genomics, Breakthrough Genomics	RCV000858616	SCV005230481	benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003960057	SCV004769479	benign	A2ML1-related disorder	2021-01-13	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).