Submissions for variant NM_001080517.3(SETD5):c.941A>G (p.Asn314Ser)

dbSNP: rs2041315307

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249686	SCV001423682	likely pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2018-04-18	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS2, PM2, PP3, BP1] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], is predicted to be damaging by multiple functional prediction tools [PP3], is a missense alteration in a gene for which primarily truncating variants are known to cause disease [BP1].
GeneDx	RCV003128758	SCV003805473	pathogenic	not provided	2023-02-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32371413)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003128758	SCV004640761	uncertain significance	not provided	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 314 of the SETD5 protein (p.Asn314Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SETD5-related neurodevelopmental syndrome (PMID: 32371413; Invitae). This variant is also known as c.647A>G (p.Asn216Ser). ClinVar contains an entry for this variant (Variation ID: 973265). 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) has been performed at Invitae 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 SETD5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001249686	SCV005367974	likely pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2024-06-19	no assertion criteria provided	clinical testing