Submissions for variant NM_033084.5(FANCD2):c.1777C>T (p.Pro593Ser) (rs147523071)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459559	SCV000547226	uncertain significance	Fanconi anemia	2018-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 593 of the FANCD2 protein (p.Pro593Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs147523071, ExAC 0.1%). This variant has not been reported in the literature in individuals with FANCD2-related disease. ClinVar contains an entry for this variant (Variation ID: 134313). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics	RCV000764454	SCV000895516	uncertain significance	Fanconi anemia, complementation group D2	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000764454	SCV000898676	uncertain significance	Fanconi anemia, complementation group D2	2018-11-07	criteria provided, single submitter	clinical testing	FANCD2 NM_033084.4 exon 20 p.Pro593Ser (c.1777C>T): This variant has not been reported in the literature and is present in 0.1% (184/129068) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-10103845-C-T). This variant is present in ClinVar (Variation ID:134313). This variant amino acid Serine (Ser) is present in several species including multiple primates and other mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
ITMI	RCV000120987	SCV000085155	not provided	not specified	2013-09-19	no assertion provided	reference population

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