Submissions for variant NM_144670.6(A2ML1):c.1970G>A (p.Arg657His)

gnomAD frequency: 0.00005  dbSNP: rs372629661

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001905086	SCV002129581	uncertain significance	not provided	2023-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 657 of the A2ML1 protein (p.Arg657His). This variant is present in population databases (rs372629661, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with A2ML1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1363785). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002236028	SCV002511962	benign	not specified	2022-04-18	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.1970G>A (p.Arg657His) results in a non-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 9.2e-05 in 249348 control chromosomes, predominantly at a frequency of 0.00043 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 100-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. c.1970G>A has been reported in the literature in an individual affected with Noonan Syndrome, however this patient also carried a pathogenic variant (SOS1 c.806T>C, p.Met269Thr), which could explain the phenotype (Papadopoulos_2022). In addition, a co-occurrences with another pathogenic variant has been reported (PTPN11 c.854T>C, p.Phe285Ser; in an internal sample), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002236028	SCV002723428	uncertain significance	not specified	2023-10-01	criteria provided, single submitter	clinical testing	The p.R657H variant (also known as c.1970G>A), located in coding exon 16 of the A2ML1 gene, results from a G to A substitution at nucleotide position 1970. The arginine at codon 657 is replaced by histidine, 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.