Submissions for variant NM_000053.4(ATP7B):c.1607T>C (p.Val536Ala) (rs138427376)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER_CC_NCGL; University of Washington Medical Center	RCV000029352	SCV000190070	uncertain significance	Wilson disease	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant belongs in a lower pathogenicity class
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000514302	SCV000609818	likely benign	not provided	2017-09-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000029352	SCV000796670	likely benign	Wilson disease	2017-12-28	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000374856	SCV000331695	benign	not specified	2016-05-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000514302	SCV000564676	uncertain significance	not provided	2018-12-20	criteria provided, single submitter	clinical testing	The V536A variant in the ATP7B gene has been reported previously in association with Wilson disease; however, clinical information was not provided nor was information regarding the presence of a second variant in this individual (Davies et al., 2008). The V536A variant is observed in 296/25,790 (1.1%) alleles from individuals of Finnish background and 939/276,998 (0.39%) total alleles, including two unrelated homozygous individuals, in large population cohorts (Lek et al., 2016). The V536A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret V536A as a variant of uncertain significance.
GenomeConnect, ClinGen	RCV000029352	SCV000606967	not provided	Wilson disease		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America	RCV000374856	SCV000051998	likely benign	not specified	2018-04-16	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1607T>C (p.Val536Ala) results in a non-conservative amino acid change located in the Heavy-metal-associated domain (HMA) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 277053 control chromosomes, predominantly at a frequency of 0.011 within the Finnish subpopulation in the gnomAD database, including 1 homozygote (2 overall). The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 2.037 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.1607T>C has been reported in the literature in individuals affected with Wilson Disease (Davies_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x uncertain significance, 1x likely benign, 2x benign). Based on the evidence outlined above, the variant was classified as likely benign.
Integrated Genetics/Laboratory Corporation of America	RCV000514302	SCV000694399	uncertain significance	not provided	2016-08-11	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.1607T>C (p.Val536Ala) variant involves the alteration of a non-conserved nucleotide. The altered amino acid is located in the heavy metal-associated domain. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 360/120802 control chromosomes, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.0128515 (85/6614) without homozygous occurrences. This frequency is about 2.4 times the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006), suggesting this is possibly a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in at least one WD patient without strong evidence for pathogenicity (Davies_2008) and one patient with ADHD; this gene has not been strongnly established as a candidate gene for this phenotype (Lyon_2011). One Medical Center by reseach has classified this variant as VUS. Taken together, this variant is classified as VUS-possibly benign.
Invitae	RCV000029352	SCV000626830	benign	Wilson disease	2018-01-22	criteria provided, single submitter	clinical testing