Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review

Ferrarotti, Ilaria; Wencker, Marion; Chorostowska-Wynimko, Joanna

doi:10.1186/s13023-024-03069-1

Orphanet Journal of Rare Diseases

Table 3 HGVS nomenclature and frequencies of the 20 most common rare AATD variants for which HGVS nomenclature information is available

From: Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review

Variant^†	HGVS variant nomenclature^‡						NCBI allele frequency aggregator (ALFA)^¥
Variant^†	Nucleotide change (base allele, if known)	Amino acid change	Protein change	Synonymous variants (base allele)	Clinical significance	Reference SNP number	European	African	African American	Asian	East Asian	South Asian	Latin American	Total
F	c.739C > T	p.Arg247Cys	R247C		AATD: reduced inhibitory activity (LoF)	rs28929470	0.003145	0.0008	0.0008	0	0	0	0	0.002943
I	c.187C > T	p.Arg63Cys	R63C		AATD: protein deficiency (LoF and mild GoF)	rs28931570	0.002012	0.002	0.002	0.0005	0.004	0	0	0.001786
M_Malton	c.227_229del (M2)	p.Phe76del	F76del	M_Cagliari (M1) M_Nichinan (M1) M_palermo (M1) Q0_{La Palma} (S)	AATD: protein deficiency (LoF and GoF)	rs775982338	0.0001	0	0	0	0	0	0	0.00007
P_Lowell	c.839A > T (M1)	p.Asp280Val	D280V	PDurate (M4) Q0Cardiff (M1)	AATD: protein deficiency (LoF)	rs121912714	0.00075	0.0003	0.0003	0	0	0	0	0.00075
V	c.5154G > A (M1)	p.Gly172Arg	G172R		Conflicting interpretations of pathogenicity	rs112030253	0.001421	0.0006	0.0006	0	0	0.002	0.007	0.001324
Q0_Ourém	c.1131A > T (M3)	p.Leu377Phe	L377F		AATD: protein absence (LoF)	rs763023697	0	0	0	0	0	0	0	0
M_Heerlen	c.1178C > T (M1)	p.Pro393Leu	P393L		AATD: protein deficiency (LoF and GoF)	rs199422209	0.000167	0	0	0	0	0	0	0.000141
M_Procida	c.194 T > C	p.Leu65Pro	L65P		AATD: protein deficiency (LoF)	rs28931569	0.00009	0.00003	0.00003	0	0	0	0	0.00011
X	c.682G > A	p.Glu228Lys	E228K		Uncertain significance	rs199422208	0.00003	0	0	0	0	0	0	0.00004
S_Iiyama	c.230C > T	p.Ser77Phe	S77F		AATD: protein deficiency (LoF and GoF)	rs55819880	0	0	0	0	0	0	0	0
M_Würzburg	c.1177C > T	p.Pro393Ser	P393S	M_{Vall d'Hebron}	AATD: protein deficiency (LoF and GoF)	rs61761869	0.000623	0	0	0	0	0	0.001	0.000563
E_Tokyo	c.1075A > G (M1)	p.Lys359Glu	K359E		Uncertain significance	rs200945035	0.01061	0	0	0.0019	0.0032	0	0	0.00924
Q0_Bellingham	c.721A > T	p.Lys241ter	K241*		AATD: protein absence (LoF)	rs199422211	0.0001	0	0	0	0	0	0	0.00008
M_Whitstable	Intron mutation: 26 bp deletion and 2 bp insertion in intron IV				Uncertain significance	GenBank: AF159454.1	not available
T	c.863A > T (M4 and M3)	p.Glu288Val	E288V		AATD: protein deficiency (LoF and GoF)	rs17580	0.03737	0.0092	0.0095	0	0	0	0.052	0.03397
P_Brescia	c.745G > C	p.Gly249Arg	G249R		AATD: protein deficiency (LoF and GoF)	rs764220898	0.0001	0	0	0	0	0	0	0.00007
Q0_Clayton	c.1158dup (M1 Val)	p.Glu387Argfs	E387Rfs		AATD: protein absence (LoF)	rs764325655	0	0	0	0	0	0	0	0
Q0_{Granite Falls}	c.552del	p.Asp183_Tyr184insTer	Y184*	Q0_Amersfoort	AATD: protein absence (LoF)	rs267606950	0	0	0	0	0	0	0	0
St. Albans	c.840C > T and c.1093G > A	p.Asp280Asp and p.Asp365Asn	D280D and D365N		Likely benign	rs1049800and rs143370956	0.00037	0.09803	0.09704	0.026	0.022	0.012	0.039	0.0142
Q0_Mattawa	c.1131A > T (M1 Val)	p.Leu377Phe	L377F		AATD: protein absence (LoF)	rs763023697	0	0	0	0	0	0	0	0

^†Variants identified by IEF in the top 20 of the most common rare AATD variants (the E, C, M_N, P, G, and L variants) were not included in this list since no HGVS variant nomenclature is available. Q0/rare (unidentified Null or rare) variants at the time of source article publication were also not included in this list
^‡HGVS recommendations for the description of sequence variants includes the first 24 residues of the signal peptide [28]; in AATD it is common to employ residue numbering according to the mature protein (i.e., without the first residues of the signal peptide) [4]. This table reports residue numbering according to HGVS recommendations. Clinical significance information provided by the ClinVar database; pathogenic variants described as LoF and/or GoF according to the mutation effect[4]
^¥NCBI ALFA was accessed at https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/ALFA_20230706150541/, November 2023
*Stop codon
AATD Alpha 1 Antitrypsin Deficiency, HGVS Human Genome Variation Society, GoF gain of function (for increased polymerization susceptibility and altered inhibitory activity variants), IEF isoelectric focusing, LoF loss of function (for deficiency Null and dysfunctional variants with reduced inhibitory activity), n/a not applicable, NCBI National Center for Biotechnology Information, SNP single nucleotide polymorphism

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ISSN: 1750-1172

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