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Table 1 Pathogenic and likely pathogenic classified variants identified in Long Life Family Study

From: Prevalence of clinically actionable disease variants in exceptionally long-lived families

SNP ID*

Gene

Amino Acid Change

Random LLFS Sampling Frequency

Population Frequency

p-value

ACMG Variant Classification: Criteria*

Number of LLFS Participants with Variant

rs28897686: NM_007294.3:c.3748G > T

BRCA1

p.Glu1250*

2.57 × 10−4

7.90 × 10−6

1

P: PVS1, PM2, PP5

3 heterozygotes

rs764575966: NM_003001.3:c.397C > T

SDHC

p.Arg133*

7.71 × 10−4

3.20 × 10−5

0.05

P: PVS1, PM2, PP5

3 heterozygotes

rs74315294: NM_000098.3:c.338C > T

CPT2

p.Ser113Leu

3.96 × 10−3

1.38 × 10− 3

0.11

P: PM1, PM2, PP3, PP5

391 heterozygotes

3 homozygotes

rs121434280: NM_001127328.2:c.211 T > C

ACADM

p.Tyr71His

2.06 × 10−4

4.87 × 10− 4

1

LP: PS3, PM2, PP5, BP4

136 heterozygotes

rs201375579: NM_001127328.2:c.809A > G

ACADM

p.Asp270Gly

4.30 × 10−5

2.97 × 10−4

1

LP: PS3, PM2

79 heterozygotes

rs138058572: NM_001270447.1:c.1427G > A

ACADVL

p.Arg476Gln

2.98 × 10−4

7.20 × 10−6

N/A

LP: PS4, PM2, PP3

1 heterozygote

rs28904921: NM_000051.3:c.7271 T > G

ATM

p.Val2424Gly

2.20 × 10−5

5.06 × 10− 5

1

LP: PS3, PM2,PP3,PP5

14 heterozygotes

rs137852849: NM_001164675.1:c.836C > T

SUMF1

p.Ala279Val

2.24 × 10−4

1.12 × 10− 4

1

LP: PS3, PM2,PP5

31 heterozygotes

rs17847577: NM_000553.4:c.1105C > T

WRN

p.Arg369*

1.73 × 10−4

1.88 × 10− 4

1

P: PVS1, PM2, PP5

53 heterozygotes

  1. *P Pathogenic, LP Likely Pathogenic
  2. PVS1: nonsense (stop-gain) mutation where loss of function is a known mechanism of disease
  3. PM2: Low allele frequency in genomic databases
  4. PP5: Reputable source(s) classified variant as pathogenic
  5. PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
  6. PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
  7. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
  8. BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
  9. PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
  10. In-silico algorithms used for PP3 criterion:
  11. CPT2 NM_000098.3:c.338C > T: Pathogenic prediction from multiple computational programs (PhyloP: C; SIFT: D; PolyPhen-2: D; Likelihood Ratio Test (LRT): D; MutationTaster: D; GERP: D)
  12. ACADM NM_001127328.2:c.211 T > C: Benign prediction from multiple computational programs (PhyloP: C; SIFT: T; PolyPhen-2: B; Likelihood Ratio Test (LRT): N; MutationTaster: D; GERP: D)
  13. ACADVL NM_001270447.1:c.1427G > A: Pathogenic prediction from multiple computational programs (PhyloP: C; SIFT: D; PolyPhen-2: D; Likelihood Ratio Test (LRT): D; MutationTaster: D; GERP: D)
  14. ATM NM_000051.3:c.7271 T > G: Pathogenic prediction from multiple computational programs (PhyloP: C; SIFT: D; PolyPhen-2: D; Likelihood Ratio Test (LRT): D; MutationTaster: N; GERP: D)
  15. PhyloP: Conserved (C) or not conserved (N); SIFT: Deleterious (D) or tolerated (T); PolyPhen-2: Damaging (D), possibly damaging (P), or benign (B); Likelihood Ratio Test (LRT): Deleterious (D) or neutral (N); MutationTaster: Deleterious (D) or neutral (N); GERP: Deleterious (D) or neutral (N)
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BMC Medical Genomics

ISSN: 1755-8794

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