Submissions for variant NM_144670.6(A2ML1):c.2719_2720del (p.Gly907fs)

dbSNP: rs560609581

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293497	SCV001482081	benign	not specified	2021-02-08	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.2719_2720delGG (p.Gly907SerfsX20) 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 (e.g. c.1444_1445delAG (p.Ser482ProfsX2), c.3676_3677delGC (p.Ala1226GlnfsX34), c.4261C>T (p.Gln1421X)). The variant allele was found at a frequency of 7.2e-05 in 249444 control chromosomes, predominantly at a frequency of 0.00014 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 35 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. To our knowledge, no occurrence of c.2719_2720delGG in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001351214	SCV001545661	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly907Serfs*20) 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 (rs560609581, gnomAD 0.02%). 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: 997876). 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.