Supplemental Table 1. Secondary Findings of Enrolled Parents. All Returned Variants Identified
Supplemental Table 1. Secondary findings of enrolled parents. All returned variants identified in the study are listed.
Age, Gender / Gene / Variant Info / Associated Phenotype (MIM) / Pathogenicity score(ACMG codes) / Transmitted to DD/ID-affected child / CADD Scores / ClinVar Evidence (RCV)a / Publication Evidence (PMID)a / Population frequencya
ACMG Gene List
40-M / BRCA1 c / NM_007294.3(BRCA1):c.5266_5267insC (p.Gln1756Profs) / Familial breast and ovarian cancer (604370) / Pathogenic (PVS1, PP1, PP5) / No / 36 / RCV000256573.2 / 21119707
8531967; 15133502 / NA (1KG); 0.000156 (ExAC)
47- M / BRCA2 c / NM_000059.3(BRCA2):c.657_658delTG (p.Val220Ilefs) / Familial breast and ovarian cancer (612555) / Pathogenic (PVS1, PP1, PP5) / No / 13.02 / RCV000031637.8 / 9667259; 22923021; 23767878; 24504028 / NA (1KG); NA (EVS)
38- F / BRCA2 / NM_000059.3(BRCA2):c.8488-1G>A / Familial breast and ovarian cancer (612555) / Pathogenic (PVS1, PS3, PM2, PP1, PP3, PP5) / Yes / 19.45 / RCV000258314.1 / 24607278;
24916970 / NA (1KG); NA (EVS)
30- F / DSG2 / NM_001943.4(DSG2):c.2954delT (p.Val986Trpfs) / Dilated cardiomyopathy, 1BB; Arrhythmogenic right ventricular dysplasia 10 (612877; 610193) / Pathogenic (PVS1, PM2, PP3, PP5) / Yes / 14.51 / RCV000485291.1 / 23788249; 20301310 / NA (1KG); NA (EVS)
50- M / DSG2 / NM_001943.4(DSG2):c.3055_3058delAGAG (p.Glu1020Alafs) / Dilated cardiomyopathy, 1BB; Arrhythmogenic right ventricular dysplasia 10 (612877; 610193) / Pathogenic (PVS1, PS3, PM2, PP3, PP5) / Yes / 43 / RCV000208503.1 / 20864495; 21397041; 23381804 / NA (1KG); NA (EVS)
47- M / KCNQ1 / NM_000218.2(KCNQ1):c.19C>T (p.Pro7Ser) / Long QT syndrome 1 (192500) / VUSb
(PM2, PP3, PP5) / Yes / 17.8 / Multiple submissions / 19716085; 18452873; / NA (1KG); NA (ExAC)
32-F / KCNQ1 / NM_000218.2(KCNQ1):c.1096C>T (p.Arg366Trp) / Long QT syndrome 1 (192500) / Pathogenic
(PS3, PM5, PM2, PP5) / Yes / 17.56 / Multiple submissions / 23788249; 24932360; 2951754 / NA (1KG); NA (EVS)
33- M / MSH2 c / NM_000251.2(MSH2):c.1708delT (p.Tyr570Metfs) / Hereditary nonpolyposis colorectal cancer, type 1 (120435) / Pathogenic (PVS1, PM2, PP3) / Yes / 25.1 / n/a / 1059400; 8723682 / NA (1KG); NA (EVS)
43- M / PMS2 / NM_000535.6(PMS2):c.736_741delCCCCCTinsTGTGTGTGAAG (p.Pro246Cysfs) / Hereditary nonpolyposis colorectal cancer, type 4 (614337) / Pathogenic (PVS1, PM1, PP5) / No / 27.7 / RCV000009829.4 / 18178629 / NA (1KG); NA (EVS)
52- M / RET / NM_020975.4(RET):c.1826G>A (p.Cys609Tyr) / Medullary thyroid carcinoma; Susceptibility to Hirschsprung disease 1 (155240; 142623) / Pathogenic
(PS3, PM2, PM5, PP1, PP3,PP5) / No / 16.48 / Multiple submissions / 16979782; 7907913; 9384613 / NA (1KG); NA (EVS)
52- F / SCN5A / NM_000335.4(SCN5A):c.3908C>T (p.Thr1303Met) / Long QT syndrome 3 (603830) / VUSb
(PM1, PP3, PP5) / Yes / 16.01 / RCV000148846.1 / 19716085; 10508990 / NA (1KG); 0.000225 (ExAC)
ClinVar/OMIM disease gene, Non-ACMG
31- M / ACTN1 / NM_001130004.1(ACTN1):c.313G>A (p.Val105Ile) / Bleeding disorder, platelet type, 15 (615193) / Pathogenic
(PS1, PS3, PM2, PP3, PP5) / No / 21.5 / RCV000034866.28 / 23434115 / NA (1KG); NA (ExAC)
52- M / ANK2 / NM_001148.4(ANK2):c.4373A>G (p.Glu1458Gly) / Cardiac arrhythmia, ankryin-B-related; Long QT syndrome 4 (600919) / Likely Pathogenic (PS3, PP1, PP3, PP5) / No / 21.5 / Multiple submissions / 12571597; 18832177; 17242276; 23861362; 15178757 / 0.0014 (1KG); 0.0004 (ExAC)
33- F / BARD1 / NM_000465.3(BARD1):c.1935_1954dup (p.Glu652Valfs) / Breast cancer susceptibility (114480) / Pathogenic (PVS1, PP1, PP5) / No / 35 / RCV000200198.3; RCV000115621.5 / 20077502 / NA (1KG); 0.000058 (gnomAD)
36- F / BARD1 / NM_000465.2(BARD1):c.1212C>G (p.Tyr404Ter) / Breast cancer susceptibility (114480) / Pathogenic (PVS1, PP1, PP5) / Yes / 35 / RCV000195626.1; RCV000132107.3 / 21344236; 22006311; 20077502; 8944023 / NA (1KG); NA (EVS)
29-F / CLCN1 / NM_000083.2(CLCN1):c.1238T>G (p.Phe413Cys) / Myotonia congenita, dominant (160800) / Pathogenic
(PS1, PS3, PP3, PP4, PP5) / Yes / 29.5 / RCV000184008.1 / 8301644; 1379744 / NA (1KG); 0.00032 (ExAC)
30- M / DDX41 / NM_016222.3(DDX41):c.415_418dupGATG (p.Asp140Glyfs) / Susceptibility to familial myeloproliferative/lymphoproliferative neoplasm (616871) / Pathogenic (PVS1, PP1, PP5) / No / 17.47 / RCV000193600.1 / 25920683; 26712909 / NA (1KG); 0.000082 (ExAC)
41- M / HARS c / NM_002109.4(HARS):c.410G>A (p.Arg137Gln) / Charcot-Marie-Tooth, axonal, type 2W (616625) / Pathogenic (PS1, PS3, PP3, PP4, PP5) / No / 35 / RCV000033152.4 / 12056811; 26072516; 22930593 / 0.0005 (1KG); 0.000079 (gnomAD)
37- F / MC4R / NM_005912.2(MC4R):c.812G>A (p.Cys271Tyr) / Obesity, autosomal dominant (601665) / Pathogenic
(PS1, PM1, PM2, PP1, PP3, PP5) / Yes / 20.7 / RCV000015405.26 / 12646665 / NA (1KG); NA (gnomAD)
35- F / MFN2 / NM_014874.3(MFN2):c.2219G>C (p.Trp740Ser) / Charcot-Marie-Tooth disease, axonal, type 2A2A (609260) / Pathogenic
(PS3, PM1, PM2, PP3, PP4, PP5) / No / 27 / RCV000002357.5 / 15064763; 22206013; 16714318; 21508331 / NA (1KG); NA (gnomAD)
39- M / MYBPC3 / NM_000256.3(MYBPC3):c.1624G>C (p.Glu542Gln) / Hypertrophic cardiomyopathy 4; Dilated cardiomyopathy 1MM (115197; 615396) / Likely pathogenic
(PS3, PP3, PP5) / No / 19.02 / Multiple submissions / 9048664 / NA (1KG); 0.000025 (ExAC)
36- F / PKD2 / NM_000297.3(PKD2):c.1319+1G>A / Polycystic kidney disease 2 (613095) / Pathogenic (PVS1, PM2, PP3, PP4) / No / 19.52 / n/a / 7633405 / NA (1KG); NA (EVS)
28-F / SCN4A / NM_000334.4(SCN4A):c.3938C>T (p.Thr1313Met) / Paramyotonia congenita (168300) / Pathogenic
(PS1, PS3, PM2, PP3, PP4, PP5) / Yes / 20.9 / RCV000006266.4 / 1310898; 7533571; 21220685; 8583225 / NA (1KG); NA (ExAC)
37- F / SLC22A5 / NM_003060.3(SLC2A5):c.424G>T (p.Ala142Ser); NM_003060.3(SLC2A5):c.1319C>T (p.Thr440Met); NM_003060.3(SLC2A5):c.1463G>A (p.Arg488His) / Carnitine deficiency, systemic primary (212140) / Pathogenic
(A142S, R488H; PS1, PS3, PM2, PP3, PP4, PP5) Likely pathogenic(T440M; PS3, PM2, PP3, PP4, PP5) / 2 of 3 variants / 8.6; 25.4; 26.6 / RCV000022320.6; RCV000022372.5; RCV000022386.6 / 16652335; 12210323 / [R488H-0.0037 (1KG); 0.004 (EVS)]; [A142S/T440M-NA (1KG); NA (EVS)]
35- F / SLC4A1 / NM_000342.3(SLC4A1):c.1462G>A (p.Val488Met) / Spherocytosis, type 4 (612653) / Likely Pathogenic
(PS3, PM2, PP3, PP4) / No / 26.9 / RCV000019350.29 / 9207478; 10942416 / NA (1KG); NA (ExAC)
M, male; F, female; 1KG: 1000 Genomes; EVS: Exome Variant Server; aAt time of analysis; bThis study began prior to publication of the classification system proposed by the ACMG [Richards, 2015]. For this publication, we have updated pathogenicity scores to reflect those determined using ACMG criteria. Two variants, KCNQ1 (P7S) and SCN5A (T1303M), were initially called pathogenic and likely pathogenic, respectively [Bowling, 2017], and returned to individuals. When considering ACMG guidelines, these variants are VUSs. cFour participants had a pathogenic variant on the ACMG or ClinVar/OMIM gene lists and a pathogenic variant in one of the carrier status genes.