Genomic analysis of the SMN1 gene region in patients with clinically diagnosed spinal muscular atrophy: a retrospective observational study

Table 3 Sequencing analysis of SMN1 for two patients with a genetic diagnosis of SMA

Patient	Variant location	Zygosity	Nucleotide change	CADD score	SIFT	Poly-Phen2	MaxEntScan	TogoVar	Functional studies	ACMG guideline
1	Intron 6	Heterozygous (SMN1, 1 copy)	c.835–3 C>A	22.2	‒	‒	8.26^a	rs772466166	Wijaya et al. (2021) reported a defect in exon 7 splicing, identified by SMN transcript analysis	Category PS3^b, PM2^c, PM3^d; likely pathogenic (criteria ii)
2	Exon 3	Homozygous (SMN1, 2 copies)	c.284 G>A	24.4	Deleterious	Probably damaging	‒	‒	‒	Category PM1^e, PM2^c, PM5^f; likely pathogenic (criteria iv)

ACMG, American College of Medical Genetics; CADD, Combined Annotation Dependent Depletion; Poly-Phen2, Polymorphism Phenotyping v2; PM, pathogenic moderate; PS, pathogenic strong; SMN1, survival motor neuron 1; SIFT, Sorting Intolerant from Tolerant
^aReported in Wijaya et al. (2021)
^bThe functional study reported in Wijaya et al. (2021) shows this variant has a deleterious effect
^cThe allele frequencies of these variants have not been reported in any control population
^dOne allele is deleted and there is a point mutation in the other allele
^eThe location of this variant is in the highly conserved Tudor domain of SMN (amino acids 92–144; Sun et al. [2005])
^fAn alternative pathogenic variant at this location (p.G95R) was previously identified in a patient with type 3 SMA, as described in Sun et al. (2005)

ISSN: 1750-1172