Submissions for variant NM_000321.3(RB1):c.1072C>T (p.Arg358Ter)

dbSNP: rs121913301

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV000013951	SCV000087370	pathogenic	Retinoblastoma	2024-05-20	criteria provided, single submitter	clinical testing	Case and Pedigree Information: BILATERAL CASES:17, UNILATERAL CASES:4, TOTAL CASES:21, PEDIGREES:20 (one pedigree contains both unilateral and bilateral cases). ACMG Codes Applied:PVS1, PM2, PS4S
Eurofins Ntd Llc (ga)	RCV000725187	SCV000334770	pathogenic	not provided	2015-09-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013951	SCV000551815	pathogenic	Retinoblastoma	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg358*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13076). This premature translational stop signal has been observed in individual(s) with unilateral or bilateral retinoblastoma (PMID: 7795591, 22219649, 22328814, 24078560, 24791139, 25928201, 26530098, 27582626).
Ambry Genetics	RCV000492492	SCV000580766	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	The p.R358* pathogenic mutation (also known as c.1072C>T), located in coding exon 11 of the RB1 gene, results from a C to T substitution at nucleotide position 1072. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been reported in numerous unrelated individuals diagnosed with both unilateral and bilateral retinoblastoma (Blanquet V et al. Hum. Mol. Genet. 1995 Mar;4:383-8; Dommering CJ et al. J. Med. Genet. 2014 Jun;51:366-74; Devarajan B et al. BMC Cancer 2015 Apr;15:320; Sagi M et al. Fam. Cancer 2015 Sep;14:471-80; Kalsoom S et al. Mol. Vis. 2015 Sep;21:1085-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000013951	SCV000853201	pathogenic	Retinoblastoma	2023-06-02	criteria provided, single submitter	clinical testing	The RB1 c.1072C>T (p.Arg358Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been identified in multiple individuals with retinoblastoma (PMID: 7795591, 22219649, 22328814, 24078560, 24791139, 25928201, 26530098, 27582626, internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000725187	SCV001762062	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000725187	SCV002599671	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22219649, 19280657, 23532519, 18503160, 12402348, 23981928, 33493472, 22328814, 25525159, 7795591, 25754945, 24078560, 15884040, 14769601, 2594029, 27582626, 26396485, 16682285, 9311732, 25928201, 12541220, 34308366, 33466343, 33456302)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000013951	SCV005086571	pathogenic	Retinoblastoma	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinoblastoma (MIM#180200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. A small proportion of families have a ‘low penetrance’ phenotype, although null alleles are almost always fully penetrant (PMID: 20301625). (I) 0115 - Variants in this gene are known to have variable expressivity whereby affected individuals can develop unilateral, bilateral or trilateral disease (PMID: 20301625; OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least ten NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by at least five clinical diagnostic laboratories (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000013951	SCV000034198	pathogenic	Retinoblastoma	1989-12-21	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000013951	SCV000504838	likely pathogenic	Retinoblastoma	2015-07-14	no assertion criteria provided	literature only