Submissions for variant NM_138477.2(CDAN1):c.2015C>T (p.Pro672Leu)

gnomAD frequency: 0.00013  dbSNP: rs120074167

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425270	SCV000521304	likely pathogenic	not provided	2018-04-02	criteria provided, single submitter	clinical testing	The P672L variant in the CDAN1 gene has been reported previously, as P671L using alternate nomenclature, in trans with a second variant in an Israeli Bedouin patient with congenital dyserythropoietic anemia (CDA) type 1 (Dgany et al., 2002) and is considered a recurring European variant accounting for 12% of mutant alleles (Tamary and Dgany, 2016). The P672L variant was also observed in multiple additional patients with childhood onset CDA, and although a second CDAN1 variant was reported in all patients, including the F52L variant in multiple individuals, it is unclear whether compound heterozygosity was confirmed with parental studies (Tamary et al., 2005; Roy et al., 2016). The P672L variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P672L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this substitution occurs at a position that is conserved across mammalian species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The P672L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000020953	SCV001149701	pathogenic	Congenital dyserythropoietic anemia, type I	2018-01-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000425270	SCV002573756	likely pathogenic	not provided	2021-04-29	criteria provided, single submitter	clinical testing	PS4, PM1
Genetics and Molecular Pathology, SA Pathology	RCV002466391	SCV002761839	pathogenic	Anemia, congenital dyserythropoietic, type 1a	2022-06-03	criteria provided, single submitter	clinical testing
Invitae	RCV000425270	SCV003273283	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 672 of the CDAN1 protein (p.Pro672Leu). This variant is present in population databases (rs120074167, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia type I (PMID: 12434312, 31900952, 33401150). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 2129C>T, Pro671Leu. ClinVar contains an entry for this variant (Variation ID: 3179). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV002466391	SCV003823037	likely pathogenic	Anemia, congenital dyserythropoietic, type 1a	2023-03-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002466391	SCV004564310	likely pathogenic	Anemia, congenital dyserythropoietic, type 1a	2023-02-01	criteria provided, single submitter	clinical testing	The CDAN1 c.2015C>T; p.Pro672Leu variant (rs120074167) is reported as a compound heterozygous variant with other pathogenic CDAN1 variants in the literature in several individuals affected with congenital dyserythropoietic anemia (CDA) type I (Dgany 2002, Garcia-Zamora 2020, Muramatsu 2017, Niss 2021, Olijnik 2021, Scott 2022). This variant is also reported in ClinVar (Variation ID: 3179). This variant is found predominantly in the non-Finnish European population with an allele frequency of 0.01% (17/121,360 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.826). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Dgany O et al. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am J Hum Genet. 2002 Dec. PMID: 12434312 Garcia-Zamora E et al. Congenital dyserythropoietic anaemia type I with nails and bone abnormalities. Clinical and experimental dermatology. 2020 Jun. PMID: 31900952 Muramatsu H et al. Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. Genet Med. 2017 Jul. PMID: 28102861 Niss O et al. Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR). Blood Cells Mol Dis. 2021 Mar. PMID: 33401150 Olijnik AA et al. Genetic and functional insights into CDA-I prevalence and pathogenesis. J Med Genet. 2021 Mar. PMID: 32518175 Scott C et al. Functional impairment of erythropoiesis in Congenital Dyserythropoietic Anaemia type I arises at the progenitor level. Br J Haematol. 2022 Jul. PMID: 35417566
OMIM	RCV000020953	SCV000023487	pathogenic	Congenital dyserythropoietic anemia, type I	2002-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000020953	SCV000041578	pathologic	Congenital dyserythropoietic anemia, type I	2011-09-01	no assertion criteria provided	curation	Converted during submission to Pathogenic.