Submissions for variant NM_024757.5(EHMT1):c.580C>T (p.Pro194Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470376	SCV002767168	uncertain significance	Kleefstra syndrome 1	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_024757.4(EHMT1):c.580C>T in exon 3 of 27 of the EHMT1 gene. This substitution is predicted to create a moderate amino acid change from proline to serine at position 194 of the protein, NP_079033.4(EHMT1):p.(Pro194Ser). The proline at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predicts this variant to be benign (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote; 0 homozygotes). An alternative residue change to leucine at the same location has been reported in the gnomAD database at a frequency of 0.07% and has been reported as likely benign/benign (ClinVar). The variant has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470376	SCV004643126	uncertain significance	Kleefstra syndrome 1	2023-05-11	criteria provided, single submitter	clinical testing	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. 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 EHMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 1806092). This variant has not been reported in the literature in individuals affected with EHMT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 194 of the EHMT1 protein (p.Pro194Ser).