Submissions for variant NM_020547.3(AMHR2):c.502G>A (p.Ala168Thr)

gnomAD frequency: 0.00001  dbSNP: rs374601719

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430189	SCV000530659	likely pathogenic	not provided	2016-12-19	criteria provided, single submitter	clinical testing	The A168T variant in the AMHR2 gene has been reported previously in an individual with persistent Mullerian duct syndrome who inherited another AMHR2 variant on the opposite allele (Oros-Millan et al., 2016). The A168T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A168T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret the A168T variant as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000430189	SCV004294203	pathogenic	not provided	2024-11-06	criteria provided, single submitter	clinical testing	This sequence change affects codon 168 of the AMHR2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the AMHR2 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs374601719, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of persistent Mullerian duct syndrome (PMID: 27461869; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 388365). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AMHR2 protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.