Table 2 In silico analysis and ACMG criteria of c.2170 G>A mutat

COBALT

Conserved

Gremlin

Conserved

Polyphen

Probably damaging

Mutation Taster

Disease causing

PhD-SNP

Disease-related polymorphism

SIFT

Predicted to be damaging

Clinvar

Pathogenic

ACMG 2015 Criteria

Reference (evidence)

Variant located in critical domain

In the kinase domain, [16, 17].

Extremely low frequency

ExAC: 0.00002, gnomAD: 0.00001

Detected in trans with pathogenic variant

Reported before in [18]

Cosegregation with disease in multiple affected family members in a gene known to cause the disease.

Two family members with homozygous c.2170G > A (p. G724S) mutation are affected (Figs. 1 and 2).

Missense variants are a common mechanism of disease

Reported before in [4, 11]

Multiple lines of computational evidence support a deleterious effect on the gene or gene product.

Yes, as shown above in this table

Patients phenotype or family history is highly specific for a disease with a single genetic etiology

Yes, as described throughout the paper

Reputable source recently reports variant as pathogenic

Yes, https://clinvarminer.genetics.utah.edu/submissions-by-variant/NM_002529.4%28NTRK1%29%3Ac.2170G%3EA%20%28p.Gly724Ser%29