Submissions for variant NM_018130.3(SHQ1):c.828_831del (p.Asp277fs)

dbSNP: rs571329853

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV002260928	SCV004041485	pathogenic	Neurodevelopmental disorder with dystonia and seizures	2023-08-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003960973	SCV005062070	likely pathogenic	SHQ1-related disorder	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: SHQ1 c.828_831delTGAT (p.Asp277SerfsX27) 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, however current evidence is not sufficient to establish loss-of-function variants in SHQ1 as causative of disease. The variant allele was found at a frequency of 0.00068 in 251084 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SHQ1 causing SHQ1-Related Disorders, allowing no conclusion about variant significance. c.828_831delTGAT has been reported in the literature in at least two compound heterozygous individuals affected with SHQ1-Related Disorders (e.g., Sleiman_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Expression of this variant in the yeast homolog demonstrated a complete absence of cell growth (Sleiman_2022). ClinVar contains an entry for this variant (Variation ID: 1693525). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV005250238	SCV005900949	uncertain significance	not provided	2025-03-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Published functional studies suggest a damaging effect (PMID: 34542157); This variant is associated with the following publications: (PMID: 34740920, 31887429, 36810590, 36416405, 34542157, 38482315, 37475611, 36847845, 39326821)
OMIM	RCV002260927	SCV002540626	pathogenic	Dystonia 35, childhood-onset	2022-06-23	no assertion criteria provided	literature only
OMIM	RCV002260928	SCV002540627	pathogenic	Neurodevelopmental disorder with dystonia and seizures	2022-06-23	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003960973	SCV004770238	uncertain significance	SHQ1-related disorder	2024-01-16	no assertion criteria provided	clinical testing	The SHQ1 c.828_831delTGAT variant is predicted to result in a frameshift and premature protein termination (p.Asp277Serfs*27). This variant was reported in the compound heterozygous state in three families with early-onset dystonia (Sleiman et al. 2021. PubMed ID: 34542157; Table S2, Cloney et al. 2021. PubMed ID: 34740920; Indelicato et al. 2023. PubMed ID: 36416405). This variant was also reported in the heterozygous state in an individual with malignant pleural mesotheliomas (Guo et al. 2020. PubMed ID: 31887429). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Few chain-terminating variants in SHQ1 are reported and loss of function has not been conclusively established as a mechanism for SHQ1-related disorders. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.