. 2024 Sep 3;11(5):1035–1048. doi: 10.3233/JND-230236

Table 4.

Variants with unclear causal significance for ALS

Patient characteristics				Gene	Inheri-tance	Reference sequence	DNA variant	Protein change	Allele frequency gnomAD v2.1.1	dbSNP	ACMG criteria	ACMG classification	ClinVar	PolyPhen-2	SIFT	CADD	Splice Al	Ref.
Sex	Age of onset	Disease subtype	fALS
F	59	Spinal ALS	no	FIG4 ^L	AD	NM_014845.6	c.122T > C	p.(Ile41Thr)	1.0 e^–3	rs121908287	PM3^vstr, PS3^sup, PM2^mod	Pathogenic	Pathogenic	D (1)	D (0)	25,8	B (0)	[21]
M	29	Spinal ALS	no	FIG4 ^L	AD	NM_014845.6	c.2095C > T	p.(Arg699Cys)	3.54 e^–5	rs764799053	PM2^mod, PP3^sup	Uncertain	Uncertain	U (0.96)	D (0)	33	B (0.01)	[5]
F	59	Spinal+ FTD	no	KIF5A	AD	NM_004984.4	c.291 + 5G > A	N/A	1.2 e^–5	rs775732465	PM2^mod, PP3^sup	Uncertain	Uncertain	N/A	N/A	N/A	M (0.33)	[22]
						NG_088155.1	g.18635G > A
M	50	Bulbar	no	NEFH ^S	AD	NM_021076.4	c.1084-3C > G	N/A	1.2 e^–5	rs1347201784	PM2^mod, PP3^sup	Uncertain	-	N/A	N/A	N/A	S (0.55)	–
						NG_008404.1	g.10529C > G
M	59	Bulbar	no	NEK1 ^S	AD	NM_001199397.3	c.760G > T	p.(Glu254*)	0	–	PVS1^mod, PM2^mod	Uncertain	-	N/A	N/A	N/A	S (0.55)	–
F*	64	Bulbar+ FTD	no	OPTN	AR	NM_001008212.2	c.785C > A	p.(Ser262*)	1.42 e^–5	rs750571210	PM3^str, PVS1^vstr, PM2^mod, PP5	Pathogenic	Pathogenic	N/A	N/A	N/A	B (0)	[23]
F*	41	Bulbar	yes	OPTN	AR	NM_001008212.2	c.785C > A	p.(Ser262*)	1.42 e^–5	rs750571210	PM3^str, PVS1^vstr, PM2^mod, PP5	Pathogenic	Pathogenic	N/A	N/A	N/A	B (0)	[23]
F	38	Spinal ALS	no	SETX ^L	AD	NM_015046.7	c.4796T > C	p.(Phe1599Ser)	0	–	PM2^mod	Uncertain	–	D (0.99)	D (0)	26,8	B (0)	–
M	64	Spinal ALS	no	SETX ^L	AD	NM_015046.7	c.6865T > C	p.(Ser2289Pro)	0	–	PM2^mod	Uncertain	–	D (0.99)	U (0.025)	24,5	B (0)	–
F**	37	LMN- predomin.	no	SOD1	AD/AR	NM_000454.5	c.378C > G	p.(Asp126Glu)	0	–	PM1^mod, PP2^sup, PM2^mod, PM5^sup, PP3^sup,	Likely pathogenic	-	D (0.99)	D (0)	25,5	B (0.03)	–
				TARDBP	AD	NM_007375.4	c.169G > A	p.(Val57Ile)	0	–	PM2^mod, PP2^sup	Uncertain	–	B (0.03)	B (0.7)	21	B (0)	–
F	57	Spinal	no	SPAST	AD	NM_014946.4	c.8C > T	p.(Ser3Phe)	0	–	PM2^mod, PP2^sup	Uncertain	–	D (0.98)	D (0)	23,4	B (0.03)	–
M	64	Bulbar	no	SPG11	AR	NM_025137.4	c.2757_2775 del	p.(Leu920Thrfs*10)	0	rs1595888828	PVS1^vstr, PM3^str, PM2^mod, PP5	Pathogenic	Likely Pathogenic	N/A	N/A	N/A	B (0)	–
M	60	LMN- predomin.	no	SPG11	AR	NM_025137.4	c.3075dup	p.(Glu1026Argfs*4)	2.79 e^–5	rs312262752	PVS1^vstr, PM3^vstr, PM2^mod, PP1^sup PP5	Pathogenic	Pathogenic	N/A	N/A	N/A	B (0.06)	[24], [25]
M	29	Spinal ALS	no	TBK1	AD	NM_013254.4	c.2069T > C	p.(Met690Thr)	0	–	PM2^mod	Uncertain	–	D (0.9)	D (0.1)	24,9	B (0.02)	–
F	70	Bulbar	no	UBQLN2	XLD	NM_013444.4	c.1481C > T	p.(Pro494Leu)	0	–	PM2^mod	Uncertain	–	B (0.02)	B (0)	22,2	B (0)	[26]

All listed variants are heterozygous; LMN – lower motor neuron; * marks 2 related individuals, mother and daughter – the mother was classified as sporadic at the time of inclusion (ad hoc), the daughter developed disease 2 years later; ** marks a single patient, carrying simultaneously 2 variants (in SOD1 and TARDBP); Gene^L – limited association with ALS; Gene^S – confers susceptibility to ALS; AR – autosomal recessive; XLD – X-linked dominant; Allele frequency gnomAD v2.1.1 shows the aggregated frequency in The Genome Aggregation Database; dbSNP, Single Nucleotide Polymorphism Database reference SNP ID number for the variant; ACMG criteria; ACMG, The American College of Medical Genetics and Genomics; ClinVar – public archive of reports of the relationships among human genetic variations and phenotypes, with supporting evidence, PolyPhen-2 – an automatic tool for prediction of the possible impact of an amino acid substitution on the structure and function of a human protein; SIFT – The Sorting Intolerant from Tolerant (SIFT) algorithm predicts the effect of coding variants on protein function; CADD – the Combined Annotation Dependent Depletion for scoring the deleteriousness of single nucleotide variants, multi-nucleotide substitutions as well as insertion/deletion variants in the human genome, the lower the score, the more benign the substitution; SpliceAl, a deep learning splicing predictor algorithm; D, deleterious; U, uncertain; B, benign; M, moderate; S, strong; N/A, not applicable; ACMG criteria: pathogenic vstr – very strong, str – strong, sup – supporting, mod – moderate.