A Japanese Family With Autosomal Dominant ...

19 downloads 0 Views 95KB Size Report
PP2. Missense variant in a gene that has a low rate of benign missense variation. Only one benign missense variant (rs2287949) was hit for a total of 1593 bp of ...
Supplementary Table. Applicable criteria for classifying variants with evidence of pathogenicity according to the ACMG Standards and Guidelines (2015) used in this study. Classification

Evidence of pathogenicity

Applicable evidence in this study

Null variant (nonsense, frameshift, splice,

NA

Very strong PVS1

initiation codon, exon(s) deletion) in a gene where LOF is a known mechanism of disease Strong PS1

Same amino acid change as a previously

NA

established pathogenic variant PS2

De novo

NA

PS3

Well-established in vitro or in vivo functional

NA

studies PS4

The prevalence of the variant in affected

NA

individuals is significantly increased Moderate PM1

Located in a mutational hot spot and/or critical

The Major Facilitator Superfamily (MFS, db_xref,

functional domain

CDD:304372) at 34-232 or MFS/sugar transport protein (db_xref, CDD: 257676) at codons 35-524, (https://www.ncbi.nlm.nih.gov/protein); Transmembrane domain at codons 70-92 (http://www.cbs.dtu.dk/services/TMHMM/); 3 mutations are reported around the transmembrane domain as G64S, G89R

Downloaded From: https://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/936033/ on 07/25/2018

and D93N (Reinders A, Ward JM. Mol Med Rep 2015;12:1393-1398) PM2

Absent

from

controls

(or

extremely

low

frequency if recessive)

Absent in “dbSNP138*”, “1000 Genomes Project data (2015Aug)*”, “NHLBI-ESP project with 6500 exomes*”, “ExAC 65000 exome allele frequency data*”, and “DBexome**”

PM3

For recessive disorders, detected in trans with

NA

a pathogenic variant PM4

Protein length changes as a result of in-frame

NA

deletions/insertions in a nonrepeat region PM5

Novel missense change at an amino acid

NA

residue where a different missense change determined to be pathogenic has been seen before (eg. R38C, R38G) PM6

Assumed to be de novo (without confirmation)

NA

Cosegregation with disease in multiple affected

LOD score of 2.00~3.56 in the region (this study)

Supporting PP1

family members PP2

Missense variant in a gene that has a low rate

Only one benign missense variant (rs2287949) was hit for a

of benign missense variation

total of 1593 bp of the coding sequence of the SLC45A2 gene***

PP3

Multiple

lines

of

computational

evidence

support a deleterious effect on the gene

“Pathogenic/Disease causing/Damaging” for Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/), SIFT (http://sift.jcvi.org), PROVEAN (http://provean.jcvi.org), MCAP

Downloaded From: https://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/936033/ on 07/25/2018

(http://bejerano.stanford.edu/mcap/) and Mutation Taster (http://www.mutationtaster.org). PP4

Patient’s phenotype or family history is highly

NA

specific for a disease with a single genetic etiology PP5

Reputable source recently reports variant as

NA

pathogenic (no laboratory evidence) Note that the combing criteria of PM1, PM2, PP1, PP2 and PP3 falls into “Likely pathogenic” as (v): 2 Moderate (PM1-PM6) AND 2 Supporting (PP1-PP5) according to ACMG Standards and Guidelines 2015 (ref. 22). NA: not applicable. *The search was accomplished by the public domain software, ANNOVAR (http://annovar.openbioinformatics.org/). **Searched by The Human Genetic Variation Database (http://www.hgvd.genome.med.kyoto-u.ac.jp). ***Searched by dbSNP138 database using UCSC Genome Browser (https://genome.ucsc.edu/).

Downloaded From: https://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/936033/ on 07/25/2018