Submissions for variant NM_000052.7(ATP7A):c.1030A>G (p.Arg344Gly)

gnomAD frequency: 0.00008  dbSNP: rs782196306

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000426016	SCV000535021	uncertain significance	not provided	2016-12-20	criteria provided, single submitter	clinical testing	The R344G variant of uncertain significance in the ATP7A gene has been reported as a novel variant in a Japaneseindividual with cancer; study authors hypothesized that genetic variants in ATP7A and ATP7B may influenceefficacy/toxicity of platinum drugs used for cancer treatment (Fukushima-Uesaka et al., 2009). R344G was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, but was observed in 0.15% of alleles from individuals of East Asian ancestry in the ExomeAggregation Consortium (ExAC). The R344G variant is a non-conservative amino acid substitution, which is likelyto 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. In silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this X-linked variant is pathogenic orrare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae	RCV001089330	SCV001075352	benign	Menkes kinky-hair syndrome; Cutis laxa, X-linked; X-linked distal spinal muscular atrophy type 3	2023-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282146	SCV002572435	uncertain significance	not specified	2022-08-31	criteria provided, single submitter	clinical testing	Variant summary: ATP7A c.1030A>G (p.Arg344Gly) results in a non-conservative amino acid change located in the Heavy metal associated domain HMA (IPR006121) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 183118 control chromosomes, including 3 hemizygotes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATP7A causing Menkes Kinky-Hair Syndrome (7.6e-05 vs 0.0035), allowing no conclusion about variant significance. c.1030A>G has been reported in the literature in at least one individual affected with Menkes Kinky-Hair Syndrome (Fujisawa_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Menkes Kinky-Hair Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and classified the variant as VUS (n=1) and as benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.