Submissions for variant NM_016169.4(SUFU):c.1028G>A (p.Arg343His)

gnomAD frequency: 0.00008  dbSNP: rs79299301

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000260834	SCV000360091	uncertain significance	Medulloblastoma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466509	SCV000544991	likely benign	Gorlin syndrome; Medulloblastoma	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566455	SCV000675276	benign	Hereditary cancer-predisposing syndrome	2021-01-04	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000763641	SCV000894512	uncertain significance	Gorlin syndrome; Medulloblastoma; Familial meningioma; Joubert syndrome 32	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001354923	SCV003933407	uncertain significance	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Observed in an individual with a personal history of chondroma (PMID: 34070849); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 26336887, 34070849)
Baylor Genetics	RCV003467081	SCV004205676	uncertain significance	Familial meningioma	2023-09-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001354923	SCV004562156	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	The SUFU c.1028G>A; p.Arg343His variant (rs79299301) is reported in the literature in an individual affected with chordoma, but without clear disease association (Yepes 2021). This variant is also reported in ClinVar (Variation ID: 135285), and is found in the non-Finnish European population with an allele frequency of 0.015% (19/129150 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.473). Due to limited information, the clinical significance of this variant is uncertain at this time.
ITMI	RCV000122100	SCV000086315	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354923	SCV001549651	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SUFU p.R343H variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs79299301), Cosmic and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Illumina and Fulgent Genetics). The variant was identified in control databases in 23 of 282820 chromosomes at a frequency of 0.00008132 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 7224 chromosomes (freq: 0.000277), European (non-Finnish) in 19 of 129150 chromosomes (freq: 0.000147), African in 1 of 24960 chromosomes (freq: 0.00004) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.R343 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004737208	SCV005348989	likely benign	SUFU-related disorder	2024-08-30	no assertion criteria provided	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).