Submissions for variant NM_014159.7(SETD2):c.19C>T (p.Gln7Ter)

gnomAD frequency: 0.00023  dbSNP: rs541943893

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623624	SCV000742369	uncertain significance	Inborn genetic diseases	2016-06-08	criteria provided, single submitter	clinical testing
Invitae	RCV000652616	SCV000774487	likely benign	Luscan-Lumish syndrome	2023-12-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193986	SCV001363190	uncertain significance	not specified	2019-09-25	criteria provided, single submitter	clinical testing	Variant summary: SETD2 c.19C>T (p.Gln7X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Pathogenic loss-of-function variants in SETD2 have been reported in the literature (PMID: 26084711, 24852293). However, there is a second in-frame ATG codon (at Met 12) downstream from the variant of interest, with an appropriate context (i.e. Kozak consensus) for translational initiation that could generate an N-terminally truncated protein product (with the loss of 11 N-terminal amino acids). The variant allele was found at a frequency of 4.8e-05 in 125046 control chromosomes (gnomAD), predominantly reported in the Latino subpopulation with a frequency of 0.00054 (i.e. 5/9314 alleles). c.19C>T has been reported in the literature in an individual affected with autism spectrum disorder (ASD), however, this patient had normal nonverbal intelligence (with no information on head circumference), and also was noted to carry a de novo 16p11.2 duplication (O'Roak_2012). Therefore this report does not provide unequivocal conclusions about association of the variant with Luscan-Lumish syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) or uncertain significance (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000652616	SCV001526392	uncertain significance	Luscan-Lumish syndrome	2018-02-02	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported in one patient (12736.p1) with autism spectrum disorder and it was inherited from the patient's mother [PMID: 23160955]
New York Genome Center	RCV000652616	SCV002764552	uncertain significance	Luscan-Lumish syndrome	2022-09-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003139952	SCV003819431	uncertain significance	not provided	2020-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533296	SCV004719680	likely benign	SETD2-related disorder	2024-01-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).