Submissions for variant NM_145886.4(PIDD1):c.2042-2A>G

gnomAD frequency: 0.00009  dbSNP: rs199752248

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV001808929	SCV002059198	likely pathogenic	PIDD1-related disorder	2022-01-03	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000087, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
New York Genome Center	RCV002266016	SCV002548875	uncertain significance	PIDD1-associated neurodevelopmental disorder	2021-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541474	SCV003263616	likely pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 of the PIDD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIDD1 are known to be pathogenic (PMID: 28397838, 29302074, 34163010). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PIDD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1333713). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989717	SCV004806871	likely pathogenic	Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004651723	SCV005149860	likely pathogenic	Inborn genetic diseases	2024-04-09	criteria provided, single submitter	clinical testing	The c.2042-2A>G intronic alteration consists of an A to G substitution two nucleotides before exon 13 (coding exon 12) of the PIDD1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the G allele has an overall frequency of 0.009% (22/254216) total alleles studied. The highest observed frequency was 0.029% (8/27218) of South Asian alleles. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003989717	SCV005373592	likely pathogenic	Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly	2023-06-02	criteria provided, single submitter	clinical testing	The observed invariant splice acceptor c.2042-2A>G variant in PIDD1 has been reported in individuals affected with PIDD1-related disorders (Teerlink CC, et. al., 2022). The c.2042-2A>G variant is reported with an allele frequency of 0.008% in the gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic. SpliceAI precits this variant to cause splice acceptor Loss (0.99). Loss of function variants have been previously reported to be disease causing. However, additional functional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV003989717	SCV005871616	likely pathogenic	Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly		criteria provided, single submitter	research	A splice site variant, g.800453T>C (NM_145886.4: c.2042-2A>G) in intron 12 of PIDD1 were found to be in heterozygous in the proband. The variant c.2042-2A>G was observed in heterozygous in the father. This variant was observed in heterozygous state in two individuals in our in-house data of 3536 exomes and absent in the gnomAD database (v4.1.0). This variant was absent in homozygous state in gnomAD and in-house database. This canonical splicing variant is predicted to cause aberrant splicing which may lead to either the formation of a truncated protein product or cause the transcript to undergo nonsense mediated mRNA decay. This variant has been reported in ClinVar (ID: VCV001333713.9) by four submitters as likely pathogenic and one submitter as variant of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV003989717	SCV005913854	uncertain significance	Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly	2023-02-06	criteria provided, single submitter	research