Table 4 The ACMG guidelines applicable to the novel variant in question, p. Thr128Asn

PS4

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

This variant is found in a sufficient number of relatives to qualify it as strong evidence of pathogenicity [36].

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.

Located in well established functional domain as reported by several studies [20, 37].

PM2

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC.

Absent from every databased queried.

PM5

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Novel mutation at same amino acid as previously reported p.Thr138Ala (HGMD Database).

PP1

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Cosegregation in a family in a gene known to cause disease.

PP3

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

Multiple lines of computational evidence presented here (Table 1).

PP4

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Patient phenotype is highly specific for a disease.