Table 1 Amino acid substitutions that were acquired and fixed in the patient

From: Adaptive evolution of SARS-CoV-2 during a persistent infection for 521 days in an immunocompromised patient

Nucleotide substitution

Resulting amino acid substitution

Incidence of the substitution

Information on functional effects known of substitutions at this site

C1185T

NSP2:A127V (conservative)

5651 (6760)

–

G5180A

NSP3:D821N (acidic > polar)

6376 (7438)

–

C5784T

NSP3:T1022I (polar > nonpolar)

28,866 (29,650)

–

G12911A

NSP9:V76I (conservative)

4164 (4739)

–

C17288T

NSP13:T351I (polar > nonpolar)

15,039 (15,637)

–

G18163A

NSP14:I42V (conservative)

8,772,722 (8,775,432)

This common substitution seems to be functionally neutral60

A18336C

NSP14:E99D (conservative)

283 (959)

–

C21660A

S:T33K (polar > basic)

460 (12,966)

–

T22220G

S:F220V (conservative)

368 (2060)

–

G22317T

S:G252V (conservative)

844,467 (858,813)

–

T22548A

S:F329Y (nonpolar > polar)

26 (1042)

–

A22812C

S:K417T* (basic > polar)

161,674 (8,035,649)

This position is crucial for ACE2 binding by forming a salt bridge with D30 of the receptor61; mutations at this position affect receptor binding, viral entry, and immune evasion49,50

A22881G

S:N440S* (conservative)

1106 (7,773,564)

Mutations at this position are well known to affect resistance to antibodies and ACE2 binding affinity62

A22893G

S:K444R* (conservative)

28,100 (616,810)

Mutations at this position are associated with antibody resistance62,63; the specific mutation K444R has been shown to reduce the neutralizing activity of vaccinated sera64

T22896C

S:V445A* (conservative)

22,867 (1,261,166)

Mutations at this position have been linked to resistance to neutralization by antibodies62; the specific mutation V445A has been shown to reduce the potency of antibodies65 and has emerged in a patient with persistent infection66

G22898A and G22899A

S:G446N* (nonpolar > polar)

576 (3,339,669)

Mutations at this position are associated with immune evasion functions67

G22917A

S:L452Q* (nonpolar > polar)

292,750 (7,837,068)

Mutations at this position are known to affect cellular immunity and infectivity68,69; the specific mutation L452Q increases binding to ACE2, evasion of HLA-A24-restricted cellular immunity, and resistance to vaccine-induced antisera69,70

T22942G

S:N460K* (polar > basic)

1,961,630 (1,967,965)

This mutation confers antibody resistance51,52,53

C22986T

S:A475V* (conservative)

28,197 (31,410)

This mutation confers resistance to several neutralizing antibodies71,72

C23013T

S:E484V* (acidic > nonpolar)

5450 (8,923,843)

Mutations at this position have been associated with neutralization escape and increased viral replicative fitness73,74; the specific mutation E484V is relatively rare, but has been found as newly emerged in patients with persistent infections66; in addition to the beneficial effects, E484V may be deleterious for ACE2 binding or RBD expression74

G23018T

S:V486F* (conservative)

0 (3,976,095)

This is a reverse mutation, from the common F486V mutation back to the wildtype F486; the V486 genotype is associated with immune evasion but also decreased binding affinity to ACE275, hence, the reverse mutation might increase binding affinity to ACE2

A23060G

S:T500A* (polar > nonpolar)

464 (2108)

This position forms a hydrogen bond with Y41 of the receptor76; the specific mutation T500A supposedly disrupts antibody binding77,78

A23223C

S:E554A (acidic > nonpolar)

1201 (278,344)

Mutations at this position are associated with escape from antibody binding79

C23230A

S:N556K (polar > basic)

3874 (5077)

This mutation had no effect in neutralization assays using several monoclonal antibodies79

C23453T

S:P631S (nonpolar > polar)

3553 (4372)

–

C23673T

S:S704L (polar > nonpolar)

356,044 (357,465)

This mutation has been shown to decrease infectivity in cell lines80

T24084G

S:L841R (nonpolar > basic)

301 (1639)

–

A24915G

S:D1118G (acidic > polar)

312 (1,221,829)

–

T25514C

ORF3a:L41P (conservative)

3424 (41,185)

–

C25624T

ORF3a:H78Y (basic > polar)

280,188 (283,802

This mutation has been associated with higher disease severity58

C28481A

N:Q70K (polar > basic)

563 (6861)

–

G28541T

N:A90S (nonpolar > polar)

19,827 (28,472)

–

G29239T

N:M322I (conservative)

9330 (14,100)

–

C29250T

N:P326L (conservative)

6840 (23,814)

Mutations at this position might reduce antibody binding81

  1. Genomic positions are relative to the SARS-CoV-2 reference sequence Wuhan-Hu-1. Resulting amino acid substitutions are rated as “conservative” in case the properties of the amino acids’ sidechains do not change with the substitution, or the change in property is indicated. The incidences given are numbers from GISAID and reflect the numbers of sequences published with the very same substitution. The number in parentheses gives the total number of sequences with any kind of substitution at this position. The date of incidence retrieval was 05/28/2024, the total number of GISAID sequences on that date was 16,760,654. An empty field “functional effects” does not mean there are no functional effects of mutations at the site, it rather means there is nothing known about the functional effects of mutations at the site to date.
  2. Asterisks mark substitutions within the spike protein’s receptor-binding domain.
  3. S spike protein, N nucleocapsid protein, NSP nonstructural protein, ORF open reading frame.
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