Case: Case 9, male, 69yo

CasePresentingHPOs: HP:0031318 (myocardial fiber disarray)

HPOsFreeText: BMI = 25.2kg/m^2, cause of death: accidental head injury, heart weight = 624g, left ventricular thickness = 1.8cm, distribution of myocyte disarray in ventricular septum, area of disarray = 7.8%, grade of fibrosis = 3

CaseNotHPOs: HP:0031296 (atrial septal hypertrophy)

CasePreviousTesting: NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

CaseGenotypingMethod: genomic DNA extracted from whole blood, PCR, NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

Variant: NM_000257.4(MYH7):c.2822G>A (p.Arg941His)

ClinVar: 636633, https://www.ncbi.nlm.nih.gov/clinvar/variation/636633/

gnomAD: 0.00001590, https://gnomad.broadinstitute.org/variant/14-23893216-C-T?dataset=gnomad_r2_1

CaseB: 40 years onset

CaseAddInfo: Late-Onset Pompe Disease

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This mutation (c.452T>C) was detected in a VHL patient with CNS hemangioblastomas and renal cell carcinoma (family no. 11). This was published in a future publication: PMID: 32179488.

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This mutation (c.452T>C) was detected in a VHL patient with CNS hemangioblastomas and renal cell carcinoma (family no. 11). This was published in a future publication: PMID: 32179488.

PatientID: None (father)

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: No significant family history.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V194G (c.581T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428810, https://www.ncbi.nlm.nih.gov/clinvar/variation/428810/

CAID: N/A

gnomAD: N/A

VariantEvidence: In silico analysis was performed using the PolyPhen-2 program and SIFT analysis. In the PolyPhen-2 analysis, the prediction score was 1.000, which indicated “probably damaging.” In addition, SIFT analysis of V194G indicated a SIFT score of 0, which indicates a seriously damaging mutation.

MutationType: missense_variant;transversion

CivicName: V194G (c.581T>G)

MultipleGeneVariants: N/A

PatientID: None (father)

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: No significant family history.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V194G (c.581T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428810, https://www.ncbi.nlm.nih.gov/clinvar/variation/428810/

CAID: N/A

gnomAD: N/A

VariantEvidence: In silico analysis was performed using the PolyPhen-2 program and SIFT analysis. In the PolyPhen-2 analysis, the prediction score was 1.000, which indicated “probably damaging.” In addition, SIFT analysis of V194G indicated a SIFT score of 0, which indicates a seriously damaging mutation.

MutationType: missense_variant;transversion

CivicName: V194G (c.581T>G)

MultipleGeneVariants: N/A

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.452T>C) was recorded in the paper as c.665T>C due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system. Any family information or relations is unknown. No other phenotypes described. This (member) was published in a future publication: PMID: 32179488.

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.452T>C) was recorded in the paper as c.665T>C due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system. Any family information or relations is unknown. No other phenotypes described. This (member) was published in a future publication: PMID: 32179488.