Submissions for variant NM_144670.6(A2ML1):c.2145del (p.Phe715fs)

dbSNP: rs759217676

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797125	SCV000936667	uncertain significance	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe715Leufs*52) in the A2ML1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in A2ML1 cause disease. This variant is present in population databases (rs759217676, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. 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: 643431). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
GeneDx	RCV000797125	SCV002008633	likely benign	not provided	2020-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226393	SCV003923298	benign	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.2145delT (p.Phe715LeufsX52) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are not commonly known mechanisms for Noonan Syndrome and Related Conditions in the A2ML1 gene. Truncations in A2ML1 have been classified as benign by our laboratory. The variant allele was found at a frequency of 0.00028 in 247198 control chromosomes, predominantly at a frequency of 0.00053 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 132-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 Non-Finnish European origin. To our knowledge, no occurrence of c.2145delT in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign and VUS. Based on the evidence outlined above, the variant was classified as benign.