Submissions for variant NM_001080517.3(SETD5):c.3305G>A (p.Gly1102Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002605466	SCV002963593	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1102 of the SETD5 protein (p.Gly1102Asp). This variant is present in population databases (rs763111545, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SETD5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1931231). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SETD5 protein function with a negative predictive value of 80%. 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004784069	SCV005397637	uncertain significance	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2024-06-25	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 3305 of the coding sequence of the SETD5 gene that results in a glycine to aspartic acid amino acid change at residue 1102 of the SET domain containing 5 protein. This is a previously reported variant (ClinVar 1931231) that has not been observed in individuals affected by a SETD5-related disorder in the published literature, to our knowledge. This variant is present in 20 of 1613868 alleles (0.0012%) in the gnomAD v4.1.0 population dataset. Bioinformatic tools are inconclusive if this amino acid change will be damaging or tolerated, and the Gly1102 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP1, PM2