Submissions for variant NM_144670.6(A2ML1):c.3380C>T (p.Ser1127Leu)

gnomAD frequency: 0.01369  dbSNP: rs61749078

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000857899	SCV000291413	benign	not provided	2025-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000228943	SCV000716038	benign	not specified	2017-02-17	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	RCV000228943	SCV001363199	benign	not specified	2019-11-18	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.3380C>T (p.Ser1127Leu) results in a non-conservative amino acid change located in the Alpha-macroglobulin-like, TED domain (IPR011626) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 249530 control chromosomes, predominantly at a frequency of 0.044 within the African or African-American subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11000-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.3380C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000857899	SCV005230528	benign	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV000228943	SCV001917588	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000228943	SCV001954042	benign	not specified		no assertion criteria provided	clinical testing