Submissions for variant NM_000052.7(ATP7A):c.3737T>C (p.Met1246Thr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003429097	SCV004117066	uncertain significance	ATP7A-related disorder	2023-08-10	criteria provided, single submitter	clinical testing	The ATP7A c.3737T>C variant is predicted to result in the amino acid substitution p.Met1246Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different missense substitution affecting the same amino acid (p.Met1246Val) was reported in an individual with neurodevelopmental delay and other features (Mederer et al 2020. PubMed ID: 33151932). At this time, the clinical significance of the c.3737T>C (p.Met1246Thr) variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003778325	SCV004578609	uncertain significance	Menkes kinky-hair syndrome; Cutis laxa, X-linked; X-linked distal spinal muscular atrophy type 3	2023-06-29	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7A protein function. This variant has not been reported in the literature in individuals affected with ATP7A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1246 of the ATP7A protein (p.Met1246Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994546	SCV004813638	uncertain significance	not specified	2024-02-01	criteria provided, single submitter	clinical testing	Variant summary: ATP7A c.3737T>C (p.Met1246Thr) results in a non-conservative amino acid change located in the haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-06 in 1,093,295 control chromosomes, including 2 hemizygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3737T>C in individuals affected with Menkes Kinky-Hair Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2636437). Based on the evidence outlined above, the variant was classified as uncertain significance.