Submissions for variant NM_000052.7(ATP7A):c.2048A>G (p.His683Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471710	SCV002769191	uncertain significance	Menkes kinky-hair syndrome	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (I) 0109 - This gene is known to be associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from a histidine to an arginine (exon 9). (I) 0251 - Variant is heterozygous. (I) 0301 - Variant is absent from gnomAD. (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (SB) 0600 - Variant is located in an annotated domain or motif (P-type_ATPase_Cu-like domain; NCBI). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0807 - Variant has not previously been reported in a clinical context. (I) 0905 - No segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - Variant is maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV003111574	SCV003789410	uncertain significance	Menkes kinky-hair syndrome; Cutis laxa, X-linked; X-linked distal spinal muscular atrophy type 3	2022-05-28	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 683 of the ATP7A protein (p.His683Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP7A-related conditions. 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 not expected to disrupt ATP7A protein function. 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.