Submissions for variant NM_016169.4(SUFU):c.1022+1G>A

dbSNP: rs587776578

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000524075	SCV000617731	pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Taylor et al., 2002, Pastorino et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12068298, 19533801, 22508808, 22829011, 24217340, 15077159, 29725392, 29186568, 21188540)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814945	SCV000955383	pathogenic	Gorlin syndrome; Medulloblastoma	2023-06-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the SUFU gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 12068298, 19533801). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 3571). This variant is also known as IVS8+1G>A. Disruption of this splice site has been observed in individual(s) with desmoplastic medulloblastoma and/or Gorlin syndrome (PMID: 19533801, 21188540). In at least one individual the variant was observed to be de novo.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003753	SCV001428792	uncertain significance	Gorlin syndrome	2019-05-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001270787	SCV001451548	pathogenic	SUFU-related disorder	2019-02-12	criteria provided, single submitter	clinical testing	The SUFU c.1022+1G>A variant is a splice donor variant that has been identified in a heterozygous state in a father and son who met criteria for nevoid basal cell carcinoma syndrome (NBCCS) and in a patient with desmoplastic medulloblastoma who did not have physical features of NBCCS at 23 months of age (Slade et al. 2007; Pastorino et al. 2009). This variant was also identified in a desmoplastic medulloblastoma sample from an individual who had a germline deletion encompassing the SUFU gene (Taylor et al. 2002). This variant was absent from 200 control alleles and is not found in the Genome Aggregation Database. RT-PCR demonstrated this splice donor variant results in a protein lacking exon 8 and produces a frameshift which leads to an early stop codon and truncation of the protein (Pastorino et al. 2009). Co-precipitation studies showed this variant was unable to bind GLI1 and GLI2 transcription factors and accumulated with these transcription factors in the nucleus, thereby preventing suppression of hedgehog signaling pathway target genes (Taylor et al. 2002). Based on the evidence, the c.1022+1G>A variant is classified as pathogenic for SUFU-related disorders.
Ambry Genetics	RCV002415392	SCV002678240	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	clinical testing	The c.1022+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the SUFU gene. This alteration has been reported in an individual with sporadic desmoplastic medulloblastoma diagnosed at age 23 months (Slade I et al. Fam Cancer, 2011 Jun;10:337-42). In addition, this alteration was detected in a father and son with a clinical diagnosis of Gorlin syndrome, and was absent in both of the father's clinically unaffected parents. Parentage was not confirmed, and the alteration was assumed to be de novo (Pastorino L et al. Am J Med Genet A, 2009 Jul;149A:1539-43). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. As such, this alteration is classified as a disease-causing mutation.
OMIM	RCV002291207	SCV000023917	pathogenic	Medulloblastoma	2009-07-01	no assertion criteria provided	literature only
OMIM	RCV003223388	SCV003918896	pathogenic	Basal cell nevus syndrome 2	2009-07-01	no assertion criteria provided	literature only