Submissions for variant NM_000052.7(ATP7A):c.3521A>T (p.Asn1174Ile)

dbSNP: rs876661235

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221793	SCV000279860	uncertain significance	not provided	2016-02-19	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ATP7A gene. The N1174I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 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 N1174I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854755	SCV002139936	uncertain significance	Menkes kinky-hair syndrome; Cutis laxa, X-linked; X-linked distal spinal muscular atrophy type 3	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with isoleucine at codon 1174 of the ATP7A protein (p.Asn1174Ile). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ATP7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 234816). 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: "Benign"; Align-GVGD: "Class C15"). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272184	SCV002557814	uncertain significance	Menkes kinky-hair syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Menkes disease (MIM#309400), Occipital horn syndrome (MIM#304150) and spinal muscular atrophy, distal (MIM#300489). The genotype-phenotype correlation is dependent on amount of residual ATPase activity, while spinal muscular atrophy, distal (MIM#300489) is due to abnormal protein trafficking (GeneReviews). (I) 0109 - This gene is associated with X-linked recessive disease. However, affected female heterozygotes and compound heterozygotes with Menkes disease (MIM#309400) have been reported (PMID: 25428120). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial varibility has been noted for Menkes disease (MIM#309400) and inter-familial observed for Spinal muscular atrophy, distal, X-linked 3 (MIM#300489) (GeneReviews).. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytoplasmic hydrolase domain (Uniprot, DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been classified a variant of uncertain significance by a diagnostic laboratory in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign