Submissions for variant NM_006208.3(ENPP1):c.2376T>A (p.Asn792Lys)

gnomAD frequency: 0.00004  dbSNP: rs137853273

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089998	SCV001245039	likely pathogenic	Arterial calcification, generalized, of infancy, 1	2019-01-05	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_006208.2(ENPP1):c.2376T>A, has been identified in exon 23 of 25 of the ENPP1 gene. The variant is predicted to result in a moderate amino acid change from an Asparagine to a Lysine at position 792 of the protein, NM_006208.2(ENPP1):p.(Asn792Lys). The Asparagine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Nuclease-like functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), however three alternative residue changes have been reported in the gnomAD database (total of 23 het and 1 hom). This variant has not been previously reported in clinical cases. A different amino acid change in the same codon, p.(Asn792Ser) has previously been described as compound heterozygous pathogenic variant in two independent infants with infantile arterial calcification (Rutsch et al., 2003). Functional data for the N792S variant showed reduced enzyme activity (Rutsch et al., 2003). Analysis of parental samples indicated this variant was paternally inherited. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. The presence of these two variants in trans confirms a compound heterozygous mode of inheritance which is consistent with generalised infant arterial calcification.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862668	SCV002201835	uncertain significance	not provided	2023-09-23	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Asn792 amino acid residue in ENPP1. Other variant(s) that disrupt this residue have been observed in individuals with ENPP1-related conditions (PMID: 12881724, 33465815), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ENPP1 protein function. ClinVar contains an entry for this variant (Variation ID: 870422). This missense change has been observed in individual(s) with autosomal recessive ENPP1-related conditions (PMID: 32573669, 33465815). This variant is present in population databases (rs137853273, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 792 of the ENPP1 protein (p.Asn792Lys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587043	SCV005076510	uncertain significance	not specified	2024-04-25	criteria provided, single submitter	clinical testing	Variant summary: ENPP1 c.2376T>A (p.Asn792Lys) results in a non-conservative amino acid change located in the DNA/RNA non-specific endonuclease domain (IPR001604) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251406 control chromosomes. c.2376T>A has been reported in the literature in three individuals affected with ENPP1-Related Disorders (Lunke_2020, Theng_2022). A different amino acid change in the same codon, c.2375A>G (p.Asn792Ser) has previously been described as compound heterozygous with either a misssense variant in two infant siblings or a nonsense variant in another infant with infantile arterial calcification (Rutsch et al., 2008). These data suggests clinical importance of this residue in ENPP1 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 870422). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV001862668	SCV005332010	likely pathogenic	not provided	2024-03-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12881724, 25741938, 33465815, 32573669)
Fulgent Genetics, Fulgent Genetics	RCV005047300	SCV005666722	likely pathogenic	Arterial calcification, generalized, of infancy, 1; Type 2 diabetes mellitus; Hypophosphatemic rickets, autosomal recessive, 2; Hypopigmentation-punctate palmoplantar keratoderma syndrome; Inherited obesity	2024-03-10	criteria provided, single submitter	clinical testing