Submissions for variant NM_014026.6(DCPS):c.947C>T (p.Thr316Met)

gnomAD frequency: 0.00006  dbSNP: rs137941190

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000412619	SCV002519480	pathogenic	Al-Raqad syndrome	2022-05-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000412619	SCV004176646	likely pathogenic	Al-Raqad syndrome	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.947C>T (p.Thr316Met) variant in DCPS gene has been reported in compound heterozygous state in individual(s) affected with DCPS relared disorders (Ahmed et. al., 2015). This variant is found to be segregating in disease related individuals. The p.Thr316Met is present with allele frequency of 0.1% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic. Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on DICS gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 316 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant in DCPS gene, the molecular diagnosis is not confirmed. The above variant has also been reported in heterozygous state in mother.
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000412619	SCV005873581	pathogenic	Al-Raqad syndrome	2020-12-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000412619	SCV005917659	uncertain significance	Al-Raqad syndrome	2023-03-13	criteria provided, single submitter	research
OMIM	RCV000412619	SCV000490310	pathogenic	Al-Raqad syndrome	2019-07-29	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000412619	SCV001142428	likely pathogenic	Al-Raqad syndrome	2020-01-06	no assertion criteria provided	curation	NM_014026.3:c.947C>T in the DCPS gene has an allele frequency of 0.01 in South Asian subpopulation in the gnomAD database. The p.Thr316Met (NM_014026.3:c.947C>T) variant has been observed in three affected individuals from a large family, in trans with a splice site variant (c.636+1G>A) and were reported to segregate with intellectual disability. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS (PMID: 25701870). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PM3; PP1.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000412619	SCV004810118	uncertain significance	Al-Raqad syndrome	2024-04-04	flagged submission	clinical testing