Submissions for variant NM_000355.4(TCN2):c.921A>C (p.Pro307=)

gnomAD frequency: 0.00010  dbSNP: rs138738105

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000351982	SCV000437889	uncertain significance	Transcobalamin II deficiency	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	RCV000351982	SCV000756655	likely benign	Transcobalamin II deficiency	2024-01-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756755	SCV000884661	likely benign	not provided	2017-12-04	criteria provided, single submitter	clinical testing	The p.Pro307Pro variant (rs138738105) does not alter the amino acid sequence of the TCN2 protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site (Alamut v2.10). This variant has not been reported in association with megaloblastic anemia in medical literature or in gene specific variation databases. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.2 percent in the South Asian population (identified on 49 out of 30,782 chromosomes), and has been reported to the ClinVar database (Variation ID: 341206). Based on these observations, the p.Pro307Pro variant is likely to be benign.
CeGaT Center for Human Genetics Tuebingen	RCV000756755	SCV004154863	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	TCN2: BP4, BP7
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000756755	SCV002034201	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000756755	SCV002038129	likely benign	not provided		no assertion criteria provided	clinical testing