Submissions for variant NM_144670.6(A2ML1):c.1937T>C (p.Ile646Thr)

gnomAD frequency: 0.00158  dbSNP: rs150488553

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000863962	SCV001004698	benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264441	SCV001442598	likely benign	not specified	2020-10-01	criteria provided, single submitter	clinical testing	Variant summary: A2ML1 c.1937T>C (p.Ile646Thr) 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 0.00036 in 249520 control chromosomes, predominantly at a frequency of 0.005 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 1250 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.1937T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000863962	SCV001911835	benign	not provided	2021-05-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487899	SCV002796690	likely benign	Otitis media, susceptibility to	2021-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001264441	SCV003912663	uncertain significance	not specified	2023-02-08	criteria provided, single submitter	clinical testing	The p.I646T variant (also known as c.1937T>C), located in coding exon 16 of the A2ML1 gene, results from a T to C substitution at nucleotide position 1937. The isoleucine at codon 646 is replaced by threonine, an amino acid with 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.
PreventionGenetics, part of Exact Sciences	RCV003918358	SCV004738084	benign	A2ML1-related disorder	2019-09-26	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).