Submissions for variant NM_006208.3(ENPP1):c.1441C>T (p.Arg481Trp)

gnomAD frequency: 0.00001  dbSNP: rs373044722

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV000660584	SCV000782696	pathogenic	Arterial calcification, generalized, of infancy, 1; Hypophosphatemic rickets, autosomal recessive, 2	2017-06-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779491	SCV000916124	likely pathogenic	Arterial calcification, generalized, of infancy, 1	2018-10-25	criteria provided, single submitter	clinical testing	The ENPP1 c.1441C>T (p.Arg481Trp) missense variant has been reported in at least two studies and is found in a compound heterozygous state in two unrelated individuals with generalized arterial calcification of infancy (Rutsch et al. 2003; Rutsch et al. 2008). One individual is reported to also have an affected sibling detected from prenatal diagnosis (Rutsch et al. 2008). The p.Arg481Trp variant was absent from 100 controls but is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project but this is based on one allele so the variant is presumed to be rare. Rutsch et al. (2003) performed RT-PCR studies on total RNA from one of the probands that showed that the p.Arg481Trp variant results in skipping of exon 15 which causes a frameshift. Transfection experiments in osteoblastic osteosarcoma cells showed the variant resulted in reduced activity to 30-40% of that associated with wild type ENPP1. The Arg481 residue lies in the catalytic domain of the ENPP1 protein and is conserved in human, mouse and rat ENPP1 and human ENPP3. Based on the evidence, the p.Arg481Trp variant is classified as likely pathogenic for generalized arterial calcification of infancy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001157114	SCV001318660	uncertain significance	Hypophosphatemic rickets, autosomal recessive, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000779491	SCV001521013	pathogenic	Arterial calcification, generalized, of infancy, 1	2020-01-17	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV001855391	SCV002246995	pathogenic	not provided	2021-11-05	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with autosomal recessive ENPP1-related conditions (PMID: 12881724, 29244957, 31826312). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in skipping of exon 15 and introduces a premature termination codon (PMID: 12881724). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 547983). This variant is present in population databases (rs373044722, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 481 of the ENPP1 protein (p.Arg481Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.
3billion	RCV001157114	SCV002521261	pathogenic	Hypophosphatemic rickets, autosomal recessive, 2	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:12881724). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:12881724). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000547983). A different missense change at the same codon (p.Arg481Gln) has been reported to be associated with ENPP1 related disorder (PMID: 26857895). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.